The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.
1. A method of treating benign prostatic hyperplasia (BPH), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)
##STR00365##
is
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-4alkoxy, cyano and —SO2—C1-4alkyl;
Rl is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl, —C(O)O—C1-4 alkyl, —C(O)—C1-4 alkyl and —C(O)-(halogenated C1-4alkyl);
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, halogenated C1-4alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl, C1-4 alkylamino, di C1-4 alkylamino, —O—C1-4 alkyl, —NRA—C(O)—C1-4 alkyl and —S(O)0-2-phenyl, wherein RA is either hydrogen or C1-4 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl, C1-4 alkylamino, di C1-4 alkylamino, —O—C1-4 alkyl, —NRB—C(O)—C1-4 alkyl and —S(O)0-2-phenyl, wherein RB is either hydrogen or C1-4 alkyl;
provided that at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, C1-4alkyl, C2-4 alkenyl, C1-4alkoxy, cyano, —C(O)O—C1-4alkyl and —S(O)0-2—C1-4alkyl;
##STR00366##
is selected from the group consisting of
##STR00367##
wherein R5′ is selected from the group consisting of halogen and C1-4alkyl; and wherein R10 is selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, —C(O)—C1-4alkyl, —C(O) -(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, cyano, nitro, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein RC and RD are each independently selected from hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
2. The method of
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-2alkoxy, cyano and —SO2—C1-2alkyl;
Rl is selected from the group consisting of C1-4alkyl and halogenated C1-2alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-2alkyl and —C(O)-(halogenated C1-2alkyl);
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano;
R4 is selected from the group consisting of halogen, cyano, nitro, benzyl, —O -phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl;
R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, C1-2alkyl, C1-2alkoxy, cyano, —C(O)O—C 1-2alkyl, —S—C1-4alkyl and —SO2—C1-4alkyl;
##STR00368##
is selected from the group consisting of
##STR00369##
wherein R5′ is halogen; and wherein R10 is selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, —C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, C1-4alkyl-S—C1-4alkyl, —C(O)O—C1-4alkyl, —C(O)-(halogenated C1-4alkyl) and trimethylsilyl;
wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-4alkyl, —O—C 1-4alkyl, —C(O)O—C 1-4alkyl, —NH—C (O)—C 1-4alkyl, —NH—C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy;
or a pharmaceutically acceptable salt thereof.
3. The method as in
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and —SO2-methyl;
R1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl;
R2 is selected from the group consisting of hydrogen, methyl, trifluoroethyl and —C(O)—CF3;
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano;
R4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO2-methyl and —SO2-phenyl;
R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO2-ethyl;
R7 is selected from the group consisting of hydrogen, chloro and ethyl;
##STR00370##
is selected from the group consisting of
##STR00371##
wherein R5′ is chloro; and wherein R10 is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl;
or a pharmaceutically acceptable salt thereof.
4. The method as in
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-2alkoxy and —SO2—C1-2alkyl;
Rl is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-2alkyl and —C(O)-(halogenated C1-2alkyl);
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano;
R4 is selected from the group consisting of halogen, cyano, nitro, benzyl, —O -phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl;
R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, C1-2alkyl, C1-2alkoxy, cyano, —C(O)O—C1-2alkyl, —S—C1-4alkyl and —SO2—C1-4alkyl;
##STR00372##
is selected from the group consisting of
##STR00373##
wherein R5′ is halogen; and wherein R10 is selected from the group consisting of hydrogen, C1-4alkyl, benzyl and —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, —C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, —C1-4alkyl-S—C1-4alkyl, —C(O)O—C1-4alkyl, —C(O)-(halogenated C1-4alkyl) and trimethylsilyl;
wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, —O—C1-4alkyl, —C(O)O—C1-4alkyl, —NH—C(O)—C 1-4alkyl, —NH-C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy;
or a pharmaceutically acceptable salt thereof.
5. The method as in
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and —SO2-methyl;
Rl is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl;
R2 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and —C(O)—CF3;
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano;
R4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO2-methyl and —SO2-phenyl;
R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO2-ethyl;
R7 is selected from the group consisting of hydrogen. chloro and ethyl:
##STR00374##
is selected from the group consisting of
##STR00375##
wherein R5′ is chloro; and wherein R10 is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl;
or a pharmaceutically acceptable salt thereof.
6. The method as in
W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy);
Rl is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl;
R2 is selected from the group consisting of hydrogen and methyl;
a is an integer from 0 to 1;
R3 is selected from the group consisting of hydrogen and trifluoromethyl;
R4 is selected from the group consisting of bromo, cyano, nitro and —SO2-phenyl;
R6 is selected from the group consisting of hydrogen, iodo, chloro and —S-ethyl;
R7 is selected from the group consisting of hydrogen and ethyl;
##STR00376##
is selected from the group consisting of
##STR00377##
wherein R5′ is chloro; and wherein R10 is selected from the group consisting of hydrogen, methyl and ethyl;
R5 is selected from the group consisting of methyl, trifluoromethyl, 1,1,2,2,2-pentafluoro-ethyl, —C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl;
or a pharmaceutically acceptable salt thereof.
7. The method as in
Rl is methyl;
R2 is selected from the group consisting of hydrogen and methyl;
a is an integer from 0 to 1;
R3 is trifluoromethyl;
R4 is selected from the group consisting of chloro, cyano and nitro;
R6 is selected from the group consisting of hydrogen, chloro, ethyl and —SO2-ethyl;
R7 is selected from the group consisting of hydrogen, chloro and ethyl;
##STR00378##
wherein R10 is selected from the group consisting of hydrogen and ethyl;
R5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-entafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2-thienyl;
or a pharmaceutically acceptable salt thereof.
8. The method as in
3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid 4-cyano-3-trifluoromethyl-phenyl)-amide;
5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide;
5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide;
3-Methyl-5[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide;
and pharmaceutically acceptable salts thereof.
9. The method of
10. A method of
|
This application is a divisional of parent application Ser. No. 11/258,448, filed on Oct. 25, 2005, now U.S. Pat. No. 7,465,809, which claims the benefit of U.S. Provisional Application 60/628,337, filed on Nov. 16, 2004, both of which are incorporated by reference herein in their entirety.
The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more androgen receptors and processes for their preparation. The compounds of the present invention are selective androgen receptor modulators (SARMs).
Androgens are the anabolic steroid hormones of animals, controlling muscle and skeletal mass, the maturation of the reproductive system, the development of secondary sexual characteristics and the maintenance of fertility in the male. In women, testosterone is converted to estrogen in most target tissues, but androgens themselves may play a role in normal female physiology, for example, in the brain. The chief androgen found in serum is testosterone, and this is the effective compound in tissues such as the testes and pituitary. In prostate and skin, testosterone is converted to dihydrotestosterone (DHT) by the action of 5α-reductase. DHT is a more potent androgen than testosterone because it binds more strongly to the androgen receptor.
Like all steroid hormones, androgens bind to a specific receptor inside the cells of target tissues, in this case the androgen receptor. This is a member of the nuclear receptor transcription factor family. Binding of androgen to the receptor activates it and causes it to bind to DNA binding sites adjacent to target genes. From there it interacts with co-activator proteins and basic transcription factors to regulate the expression of the gene. Thus, via its receptor, androgens cause changes in gene expression in cells. These changes ultimately have consequences on the metabolic output, differentiation or proliferation of the cell that are visible in the physiology of the target tissue.
Although modulators of androgen receptor function have been employed clinically for some time, both the steroidal (Basaria, S., Wahlstrom, J. T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117; Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), and non-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784) compounds have significant liabilities related to their pharmacological parameters, including gynecomastia, breast tenderness and hepatoxicity. In addition, drug-drug interactions have been observed in patients receiving anticoagulation therapy using coumarins. Finally, patients with aniline sensitivities could be compromised by the metabolites of non-steroidal antiandrogens.
Non-steroidal agonists and antagonists of the androgen receptor are useful in the treatment of a variety of disorders and diseases. More particularly, agonists of the androgen receptor could be employed in the treatment of prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne. Antagonists of the androgen receptor could be employed in male contraception, male performance enhancement, as well as in the treatment of cancer, AIDS, cachexia, and other disorders.
Nonetheless, there exists a need for small molecule, non-steroidal antagonists of the androgen receptor. We now describe a novel series of tri-substituted pyrazole derivatives as androgen receptor modulators.
The present invention is directed to compounds of formula (I)
##STR00001##
wherein
W is selected from the group consisting of O, S and NRF;
RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and —SO2—C1-4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl, —C(O)O—C1-4alkyl, —C(O)—C1-4alkyl and —C(O)-(halogenated C1-4alkyl);
a is an integer from 0 to 1;
##STR00002##
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NR AC(O)_C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NRBC(O)_C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
##STR00003##
is phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, —C(O)O—C1-4alkyl and —S(O)0-2—C1-4alkyl;
provided further that R3 is absent when a nitrogen atom is present at the 3-position of
##STR00004##
provided further that R4 is absent when a nitrogen atom is present at the 4-position of
##STR00005##
provided further that R6 is absent when a nitrogen atom is present at the 6-position of
##STR00006##
provided further that R7 is absent when a nitrogen atom is present at the 2-position of
##STR00007##
##STR00008##
is selected from the group consisting of
##STR00009##
wherein R5′ is selected from the group consisting of halogen and C1-4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —SO2—NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each RC and RD are each independently selected from hydrogen or C1-4alkyl;
and pharmaceutically acceptable salts thereof.
The present invention is further directed to compounds of formula (II)
##STR00010##
wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2;
wherein RE is selected from the group consisting of hydrogen and C1-4alkyl;
wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and —SO2—C1-4alkyl;
provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen;
alternatively, the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure;
R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
a is an integer from 0 to 1;
##STR00011##
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NRA—C(O)—C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NR BC(O)—C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
##STR00012##
is phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, —C(O)O—C1-4alkyl and —S(O)0-2—C1-4alkyl;
provided further that R3 is absent when a nitrogen atom is present at the 3-position of
##STR00013##
provided further that R4 is absent when a nitrogen atom is present at the 4-position of
##STR00014##
provided further that R6 is absent when a nitrogen atom is present at the 6-position of
##STR00015##
provided further that R7 is absent when a nitrogen atom is present at the 2-position of
##STR00016##
##STR00017##
is selected from the group consisting of
##STR00018##
wherein R5′ is selected from the group consisting of halogen and C1-4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —SO2—NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each RC and RD are each independently selected from hydrogen or C1-4alkyl;
and pharmaceutically acceptable salts thereof.
The present invention is further directed to a tautomeric mixture comprising
##STR00019##
RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and —SO2—C1-4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
a is an integer from 0 to 1;
##STR00020##
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NR AC(O)_C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NRB—C(O)—C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
##STR00021##
is phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each absent or independently selected from the group consisting of hydrogen halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, —C(O)O—C1-4alkyl and —S(O)0-2—C1-4alkyl;
provided further that R3 is absent when a nitrogen atom is present at the 3-position of
##STR00022##
provided further that R4 is absent when a nitrogen atom is present at the 4-position of
##STR00023##
provided further that R6 is absent when a nitrogen atom is present at the 6-position of
##STR00024##
provided further that R7 is absent when a nitrogen atom is present at the 2-position of
##STR00025##
##STR00026##
is selected from the group consisting of
##STR00027##
wherein R5′ is selected from the group consisting of halogen and C1-4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —SO2—NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each RC and RD are each independently selected from hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described herein. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described herein and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating disorders and conditions modulated by the androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described herein.
An example of the invention is a method for treating an androgen receptor modulated disorder selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia, hirsutism, or for male contraception, comprising administering to a subject in need thereof an effective amount of any of the compounds or pharmaceutical compositions described herein.
Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, for (j) male contraception, or for (k) male performance enhancement, in a subject in need thereof.
The present invention is directed to compounds of formula (I) and compounds of formula (II)
##STR00028##
wherein R1, R2, R3, R4, R6, R7, W, Z, a,
##STR00029##
are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and/or as a male performance enhancer.
The present invention is further directed to tautomeric mixtures comprising a compound of formula (It) and a compound of formula (IIt)
##STR00030##
wherein R1, R3, R4, R6, R7, RF, a,
##STR00031##
are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and/or as a male performance enhancer.
One skilled in the art will recognize that some of the variables (e.g. R1, R2, R3, a, etc.) appear in compounds of formula (I) and compounds of formula (II). One skilled in the art will further recognize that wherein a particular substituent is selected for a given variable for a compound of formula (I), said selection is not intended to limit the scope of said variable for compounds of formula (II). Similarly, the selection of a particular substituent for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (I).
One skilled in the art will recognize that when in the compound of formula (I) R2 is hydrogen and W is NRF and in the compound of formula (II) Z is NHRF, then the corresponding compound of formula (I) and the corresponding compound formula (II) are tautomers. One skilled in the art will further recognize that in solution, the tautomers may exist as a mixture of varying ratios, depending on the nature of the solvent. Upon isolation as a solid, only one of the tautomers is isolated, although which tautomer was isolated was not determined for the compounds of the instant application.
In an embodiment, the present invention is directed to compounds of formula (I)
##STR00032##
wherein
R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl and —C(O)O—C1-4alkyl;
a is an integer from 0 to 1;
##STR00033##
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NRA—C(O)—C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —NR BC(O)—C1-4alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
##STR00034##
is phenyl then at least one of R3 or R4 is other than hydrogen;
provided further that R3 is absent when a nitrogen atom is present at the 3-position of
##STR00035##
provided further that R4 is absent when a nitrogen atom is present at the 4-position of
##STR00036##
##STR00037##
is selected from the group consisting of
##STR00038##
wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl or benzyl;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —S(O)0-2—C1-4alkyl, —SO2—NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each RC and RD are each independently selected from hydrogen or C1-4alkyl;
and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-4alkoxy, cyano and —SO2—C1-4alkyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-2alkoxy, cyano and —SO2—C1-2alkyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and —SO2-methyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and —SO2-methyl.
In an embodiment of the present invention, W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy). In another embodiment of the present invention, W is selected from the group consisting of O and N(ethyl).
In an embodiment of the present invention W is selected from the group consisting of O and S. Preferably W is O. In another embodiment of the present invention W is selected from the group consisting of O and NRF. In another embodiment of the present invention W is NRF. Preferably, W is NRF and RF is selected form the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl and —SO2—C1-4alkyl. More preferably, W is NRF and RF is selected form the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl and —SO2-methyl.
In an embodiment of the present invention, Z is selected from the group consisting of —O-methyl, —O-ethyl, —S-ethyl, —NH2, —NH(OH), —NH-ethyl, —N(ethyl)2 and —NH(OCH3).
In an embodiment of the present invention, RE is selected from the group consisting of hydrogen and C1-4alkyl. In another embodiment of the present invention, RE is selected from the group consisting of C1-4alkyl. In another embodiment of the present invention, RE is selected from the group consisting of methyl and ethyl.
In an embodiment of the present invention, each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and —SO2—C1-4alkyl. In another embodiment of the present invention, each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-2alkoxy and —SO2—C1-2alkyl. In another embodiment of the present invention, RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl, methoxy and —SO2-methyl.
In an embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure. In another embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form 1-pyrrolidinyl or 1-piperidinyl. In another embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form 1-pyrrolidinyl.
In an embodiment of the present invention, R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of C1-4alkyl and halogenated C1-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl.
In an embodiment of the present invention, R1 is selected from the group consisting of C1-2alkyl and halogenated C1-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of C1-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (R)-methyl and (S)-methyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl and (S)-methyl.
In an embodiment of the present invention, R1 is selected from the group consisting of C1-2alkyl and halogenated C1-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of C1-4alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, ethyl and n-propyl. Preferably, R1 is selected from the group consisting of methyl, ethyl and n-propyl. More preferably, R1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl and ethyl. More preferably still, R1 is methyl.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen and C1-4alkyl. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen and methyl. Preferably, R2 is hydrogen.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl and —C(O)-(halogenated C1-4alkyl). In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-2alkyl and —C(O)-(halogenated C1-2alkyl). In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, trifluoroethyl and —C(O)—CF3.
In an embodiment of the present invention, a is 1. In another embodiment of the present invention, a is 0.
In an embodiment of the present invention,
##STR00039##
is selected from the group consisting of phenyl and pyridyl. In another embodiment,
##STR00040##
is selected from the group consisting of phenyl, 3-pyridyl and 4-pyridyl. Preferably,
##STR00041##
is phenyl. In another embodiment of the present invention,
##STR00042##
is pyridyl. In yet another embodiment of the present invention,
##STR00043##
is selected from the group consisting of 3-pyridyl and 4-pyridyl.
In an embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl. In another embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano. Preferably, R3 is absent or selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano.
In an embodiment of the present invention, R3 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano. In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano. Preferably, R3 is selected from the group consisting of hydrogen and trifluoromethyl. More preferably, R3 is trifluoromethyl.
In an embodiment of the present invention, R3 is absent or hydrogen.
In an embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen and halogenated C1-2alkyl. In another embodiment of the present invention, R3 is halogenated C1-2alkyl. In another embodiment of the present invention, R3 is trifluoromethyl.
In an embodiment of the present invention, R4 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl. In another embodiment of the present invention, R4 is absent or selected from the group consisting of halogen, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl. Preferably, R4 is absent or selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO2-methyl and —SO2-phenyl.
In an embodiment of the present invention, R4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO2-methyl and —SO2-phenyl. In another embodiment of the present invention, R4 is selected from the group consisting of halogen, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)0-2—C1-4alkyl and —S(O)0-2-phenyl. Preferably, R4 is selected from the group consisting of bromo, cyano, nitro and —SO2-phenyl. More preferably, R4 is selected from the group consisting of chloro, cyano and nitro.
In an embodiment of the present invention, R4 absent or is selected from the group consisting of cyano and halogen. In another embodiment of the present invention, R4 absent or is selected from the group consisting of cyano and chloro.
In an embodiment of the present invention, R4 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-2alkyl and cyano. In another embodiment of the present invention, R4 is cyano. In an embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, C1-4alkoxy, cyano, —C(O)O—C1-4alkyl and —S(O)0-2—C1-4alkyl.
In another embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-2alkyl, C1-2alkoxy, cyano, —C(O)O—C1-2alkyl, —S—C1-4alkyl and —SO2—C1-4alkyl. In another embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl and halogenated C1-2alkyl.
In an embodiment of the present invention, R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO2-ethyl. In another embodiment of the present invention, R6 is selected from the group consisting of hydrogen, iodo, chloro and —S-ethyl. In another embodiment of the present invention, R6 is selected from the group consisting of hydrogen, chloro, ethyl and —SO2-ethyl. In another embodiment of the present invention, R6 is hydrogen.
In an embodiment of the present invention, R7 is selected from the group consisting of hydrogen, chloro and ethyl. In another embodiment of the present invention, R7 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R7 is hydrogen.
In an embodiment of the present invention,
##STR00044##
is selected from the group consisting of
##STR00045##
In another embodiment of the present invention,
##STR00046##
is selected from the group consisting of
##STR00047##
In another embodiment of the present invention,
##STR00048##
is selected from the group consisting of
##STR00049##
In another embodiment of the present invention,
##STR00050##
is selected from the group consisting of
##STR00051##
In another embodiment of the present invention,
##STR00052##
is selected from the group consisting of
##STR00053##
In another embodiment of the present invention,
##STR00054##
In an embodiment of the present invention,
##STR00055##
is selected from the group consisting of
##STR00056##
In another embodiment of the present invention,
##STR00057##
is selected from the group consisting of
##STR00058##
Preferably,
##STR00059##
In an embodiment of the present invention,
##STR00060##
is selected from the group consisting of
##STR00061##
In another embodiment of the present invention,
##STR00062##
is selected from the group consisting of
##STR00063##
In yet another embodiment of the present invention,
##STR00064##
is selected from the group consisting of
##STR00065##
In yet another embodiment of the present invention,
##STR00066##
is selected from the group consisting of
##STR00067##
In an embodiment of the present invention, R5′ is selected from the group consisting of halogen and C1-2alkyl. In another embodiment of the present invention, R5′ is selected from the group consisting of halogen and C1-4alkyl. In another embodiment of the present invention, R5′ is selected from the group consisting of halogen and C1-2alkyl. In another embodiment, R5′ is selected from the group consisting of chloro, bromo, idoo, methyl and ethyl. Preferably, R5′ is chloro or methyl, more preferably, R5′ is chloro.
In an embodiment of the present invention R10 and R11 are each independently selected from the group consisting of hydrogen, methyl and benzyl. Preferably, R10 and R11 are each independently selected from the group consisting of hydrogen and methyl.
In an embodiment of the present invention, R10 is selected from hydrogen, C1-4alkyl, benzyl or —C(O)—CF3. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, C1-4alkyl, benzyl and —C(O)—CF3. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, C1-2alkyl and benzyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, methyl and benzyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and C1-4alkyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and methyl. Preferably, R10 is hydrogen.
In an embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, —C(O)—C1-4alkyl, —C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, —C(O)O-aryl, —C1-4alkyl-S(O)0-2—C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;
wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, cyano, nitro, —NRC—C(O)—C1-4alkyl, NRC—C(O)-(halogenated C1-4alkyl), —C(O)O—C1-4alkyl, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein RC and RD are each independently selected from hydrogen or C1-4alkyl.
In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, —C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, —C1-4alkyl-S—C1-4alkyl, —C(O)O—C1-4alkyl, —C(O)-(halogenated C1-4alkyl) and trimethylsilyl;
wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, —O—C1-4alkyl, —C(O)O—C1-4alkyl, —NH—C(O)—C1-4alkyl, —NH—C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy.
In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ethyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl.
Preferably, R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ethyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl.
In a embodiment of the present invention, R5 is selected from the group consisting of halogenated C1-2alkyl. In another embodiment of the present invention, R5 is trifluoromethyl. In another embodiment of the present invention, R5 is selected from the group consisting of halogenated C1-4alkyl and aryl; wherein the aryl is optionally substituted with one to two halogen. Preferably, R5 is selected from the group consisting of trifluoromethyl and 4-fluorophenyl.
In an embodiment of the present invention, R5 is selected from the group consisting of methyl, trifluoromethyl, 1,1,2,2,2-pentafluoro-ethyl, —C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl. In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2-thienyl.
In an embodiment of the present invention are compounds of formula (I) selected from the group consisting of 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide; 3-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention, the R1 group on the compound of formula (I) or the compound of formula (II) is in the (R) stereo-configuration. In another embodiment of the present invention, the R1 group on the compound of formula (I) or the compound of formula (II) is in the (S) stereo-configuration.
In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1-4 below.
Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. R1, R2, R3, R4, R6, R7, W, Z, a,
##STR00068##
are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
Representative compounds of the present invention are as listed in Table 1-9 below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-configurations. Where a stereogenic center is present, the (S) and (R) designations are intended to indicate that the exact stereo-configuration of the center has been determined.
TABLE 1
Representative Compounds of Formula (I)
##STR00069##
ID
R1
R3
R4
R10
R5
1
methyl
trifluoromethyl
cyano
H
4-fluoro-phenyl
2
methyl
trifluoromethyl
cyano
H
3,4-difluoro-phenyl
3
methyl
trifluoromethyl
cyano
H
4-ethyl-phenyl
4
methyl
trifluoromethyl
cyano
H
2-furyl
5
methyl
trifluoromethyl
cyano
benzyl
4-fluoro-phenyl
6
methyl
trifluoromethyl
nitro
H
H
7
methyl
trifluoromethyl
nitro
H
4-fluoro-phenyl
8
methyl
trifluoromethyl
cyano
H
trifluoromethyl
9
methyl
trifluoromethyl
cyano
H
2,3,4,5,6-
pentafluoro-phenyl
10
methyl
trifluoromethyl
cyano
H
4-methoxy-phenyl
11
methyl
trifluoromethyl
cyano
H
isobutyl
12
methyl
trifluoromethyl
cyano
H
2-fluoro-3-hydroxy-
phenyl
13
methyl
trifluoromethyl
chloro
H
4-fluoro-phenyl
14
methyl
trifluoromethyl
cyano
H
n-propyl
15
methyl
trifluoromethyl
cyano
H
ethyl
16
methyl
H
phenyl-carbonyl
H
H
17
methyl
H
phenyl-carbonyl
H
trifluoromethyl
18
methyl
H
benzyl
H
trifluoromethyl
19
methyl
H
phenyloxy-
H
trifluoromethyl
20
methyl
H
cyano
H
trifluoromethyl
21
methyl
H
cyano
H
H
23
methyl
trifluoromethyl
chloro
H
trifluoromethyl
24
methyl
chloro
chloro
H
trifluoromethyl
25
methyl
trifluoromethyl
cyano
H
cyclohexyl
28
methyl
H
phenyl-thio-
H
trifluoromethyl
30
ethyl
trifluoromethyl
cyano
H
trifluoromethyl
32
methyl
H
phenyl-sulfonyl
H
trifluoromethyl
33
methyl
trifluoromethyl
cyano
H
4-methyl-carbonyl-
amino-phenyl
34
methyl
trifluoromethyl
nitro
H
4-methyl-carbonyl-
amino-phenyl
35
(S)-methyl
trifluoromethyl
cyano
H
trifluoromethyl
36
(R)-methyl
trifluoromethyl
cyano
H
trifluoromethyl
37
methyl
trifluoromethyl
nitro
H
4-(trifluoro-methyl-
carbonyl-amino)-
phenyl
38
methyl
cyano
cyano
H
4-methyl-carbonyl-
amino-phenyl
39
methyl
trifluoromethyl
cyano
methyl
4-methyl-carbonyl-
amino-phenyl
40
methyl
trifluoromethyl
nitro
methyl
4-methyl-carbonyl-
amino-phenyl
41
methyl
trifluoromethyl
cyano
H
3-methyl-carbonyl-
amino-phenyl
42
methyl
trifluoromethyl
cyano
H
isopropyl
43
methyl
trifluoromethyl
cyano
H
4-methyl-carbonyl-
amino-benzyl
44
methyl
trifluoromethyl
chloro
H
4-methyl-carbonyl-
amino-phenyl
45
methyl
trifluoromethyl
cyano
H
4-methoxy-
carbonyl-phenyl
46
methyl
trifluoromethyl
chloro
H
4-(trifluoro-methyl-
carbonyl-amino)-
phenyl
47
methyl
trifluoromethyl
cyano
H
H
48
methyl
chloro
chloro
H
H
49
methyl
trifluoromethyl
cyano
H
2-thienyl
52
methyl
trifluoromethyl
cyano
H
2-tetrahydro-furyl
56
methyl
trifluoromethyl
cyano
H
3-methyl-4-fluoro-
phenyl
57
methyl
trifluoromethyl
nitro
H
trimethyl-silyl
73
n-propyl
trifluoromethyl
cyano
H
trifluoromethyl
74
methyl
trifluoromethyl
nitro
H
trifluoromethyl
75
methyl
trifluoromethyl
cyano
H
2,2,2-trifluoro-ethyl
76
methyl
trifluoromethyl
cyano
H
2-hydroxy-phenyl
77
methyl
trifluoromethyl
cyano
H
3-pyridyl
78
methyl
trifluoromethyl
cyano
H
cyclopentyl
79
methyl
trifluoromethyl
cyano
H
methyl-thio-ethyl-
81
(S)-ethyl
trifluoromethyl
cyano
H
trifluoromethyl
82
(R)-ethyl
trifluoromethyl
cyano
H
trifluoromethyl
83
methyl
trifluoromethyl
nitro
H
ethoxy-carbonyl-
84
methyl
trifluoromethyl
cyano
H
ethoxy-carbonyl-
85
methyl
trifluoromethyl
bromo
H
ethoxy-carbonyl-
86
methyl
trifluoromethyl
cyano
H
t-butyl
87
methyl
trifluoromethyl
cyano
H
ethyl-thio-ethyl-
89
methyl
trifluoromethyl
nitro
H
t-butyl
90
methyl
trifluoromethyl
cyano
H
t-butoxy-carbonyl-
91
methyl
trifluoromethyl
cyano
H
carboxy
92
methyl
trifluoromethyl
cyano
H
hydroxy-methyl-
96
methyl
trifluoromethyl
cyano
H
2-(t-butyl-dimethyl-
silyl)-3-fluoro-
phenyl
97
methyl
trifluoromethyl
cyano
H
2-hydroxy-3-fluoro-
phenyl
99
methyl
trifluoromethyl
cyano
H
1,1,2,2,2-
pentafluoro-ethyl
100
methyl
trifluoromethyl
nitro
H
1,1,2,2,2-
pentafluoro-ethyl
112
trifluoro-
trifluoromethyl
cyano
H
trifluoromethyl
methyl
113
trifluoro-
trifluoromethyl
cyano
H
ethoxy-carbonyl-
methyl
116
trifluoro-
trifluoromethyl
cyano
H
methyl
methyl
119
methyl
trifluoromethyl
bromo
H
trifluoromethyl
120
methyl
trifluoromethyl
cyano
ethyl
trifluoromethyl
122
(S)-methyl
trifluoromethyl
cyano
ethyl
trifluoromethyl
123
methyl
trifluoromethyl
cyano
methyl
trifluoromethyl
125
(R)-methyl
trifluoromethyl
cyano
ethyl
trifluoromethyl
131
methyl
trifluoromethyl
cyano
tri-
trifluoromethyl
fluoro-
methyl-
car-
bonyl
135
methyl
trifluoromethyl
cyano
ethyl
4-methyl-carbonyl-
amino-phenyl
146
methyl
trifluoromethyl
cyano
ethyl
methyl
TABLE 2
Representative Compounds of Formula (I)
##STR00070##
ID
R1
R2
R3
R4
R5
22
methyl
H
H
phenoxy
H
26
methyl
H
H
methyl-sulfonyl-
H
27
methyl
H
H
methyl-sulfonyl-
trifluoromethyl
29
methyl
H
H
chloro
trifluoromethyl
115
methyl
trifluoromethyl-
trifluoro-methyl
cyano
trifluoromethyl
carbonyl-
133
methyl
methyl
trifluoro-methyl
cyano
trifluoromethyl
TABLE 3
Representative Compounds of Formula (I)
##STR00071##
ID
R1
a
R3
R4
R5
51
methyl
0
trifluoromethyl
cyano
trimethyl-silyl
53
methyl
0
trifluoromethyl
cyano
3,4-difluoro-
phenyl
54
methyl
0
trifluoromethyl
cyano
2-t-butyl-
dimethyl-
silyloxy-
phenyl
55
methyl
0
trifluoromethyl
cyano
2-hydroxy-
phenyl
58
methyl
0
trifluoromethyl
cyano
ethyl
59
methyl
0
trifluoromethyl
cyano
methyl-thio-
ethyl
60
methyl
0
trifluoromethyl
cyano
methyl
61
methyl
0
trifluoromethyl
cyano
isobutyl
62
methyl
0
trifluoromethyl
cyano
n-propyl
63
methyl
0
H
phenyl-
trimethyl-silyl
carbonyl
64
methyl
0
trifluoromethyl
cyano
4-fluoro-
phenyl
65
methyl
0
H
cyano
trimethyl-silyl
66
methyl
1
H
phenyloxy-
trimethyl-silyl
67
methyl
1
H
methyl-
trimethyl-silyl
sulfonyl
68
methyl
0
trifluoromethyl
cyano
cyclohexyl
69
methyl
0
trifluoromethyl
cyano
isopropyl
98
methyl
0
trifluoromethyl
cyano
methyl
114
methyl
0
trifluoromethyl
cyano
methyl
TABLE 4
Representative Compounds of Formula (I)
##STR00072##
ID
##STR00073##
R1
R3
R4
R5
70
##STR00074##
methyl
trifluoromethyl
cyano
4-methyl-carbonyl- amino-phenyl
71
##STR00075##
methyl
trifluoromethyl
nitro
4-methyl-carbonyl amino-phenyl
72
##STR00076##
methyl
trifluoromethyl
cyano
4-methyl-carbonyl amino-phenyl
95
##STR00077##
methyl
trifluoromethyl
cyano
4-fluoro-phenyl
103
##STR00078##
methyl
trifluoromethyl
cyano
methyl
104
##STR00079##
methyl
chloro
chloro
methyl
105
##STR00080##
methyl
H
cyano
methyl
101
##STR00081##
methyl
trifluoromethyl
cyano
H
102
##STR00082##
methyl
trifluoromethyl
cyano
trifluoro-methyl- carbonyl-
107
##STR00083##
methyl
trifluoromethyl
cyano
4-methyl-carbonyl amino-benzyl
110
##STR00084##
methyl
trifluoromethyl
cyano
trifluoromethyl
111
##STR00085##
methyl
trifluoromethyl
cyano
absent
124
##STR00086##
methyl
trifluoromethyl
cyano
trifluoromethyl
134
##STR00087##
methyl
trifluoromethyl
cyano
methyl
TABLE 5
Representative Compounds of formula (I)
##STR00088##
ID No.
##STR00089##
R5
R1
R2
R6
R7
126
##STR00090##
trifluoromethyl
methyl
H
iodo
H
127
##STR00091##
trifluoromethyl
methyl
H
H
ethyl
128
##STR00092##
trifluoromethyl
methyl
H
ethyl
H
129
##STR00093##
trifluoromethyl
methyl
H
cyano
H
130
##STR00094##
trifluoromethyl
methyl
H
chloro
H
137
##STR00095##
trifluoromethyl
methyl
H
chloro
chloro
138
##STR00096##
trifluoromethyl
methyl
trifluoro- ethyl
chloro
chloro
139
##STR00097##
trifluoromethyl
methyl
H
chloro
chloro
140
##STR00098##
trifluoromethyl
methyl
H
ethyl-thio-
H
141
##STR00099##
trifluoromethyl
methyl
H
methoxy
H
142
##STR00100##
trifluoromethyl
methyl
H
ethyl- sulfonyl-
H
143
##STR00101##
trifluoromethyl
methyl
H
t-butyl- thio-
H
TABLE 6
Representative Compounds of Formula (I)
##STR00102##
ID No.
##STR00103##
R5
R1
R2
R6
R7
147
##STR00104##
H
methyl
H
methoxy- carbonyl-
H
TABLE 7
Representative Compounds of Formula (I)
##STR00105##
ID No.
##STR00106##
R5
R1
R3
R4
118
##STR00107##
trifluoromethyl
methyl
trifluoromethyl
cyano
136
##STR00108##
trifluoromethyl
methyl
chloro
chloro
144
##STR00109##
trifluoromethyl
(R)- methyl
trifluoromethyl
cyano
145
##STR00110##
trifluoromethyl
(S)- methyl
trifluoromethyl
cyano
TABLE 8
Representative Compounds of Formula (I)
ID No
Structure
80
##STR00111##
88
##STR00112##
93
##STR00113##
Representative compounds of formula (II) are as listed in Table 9 below. For convenience only one tautomeric form of the compounds listed below is specifically shown in Table 9.
TABLE 9
Representative Compounds of Formula (II)
##STR00114##
ID No.
##STR00115##
R1
R3
R4
Z
200
##STR00116##
methyl
trifluoro- methyl
cyano
—O-ethyl
201
##STR00117##
(S)-methyl
trifluoro- methyl
cyano
—O-ethyl
202
##STR00118##
(S)-methyl
trifluoro- methyl
cyano
—O-ethyl
203
##STR00119##
methyl
trifluoro- methyl
cyano
—O-methyl
204
##STR00120##
methyl
trifluoro- methyl
cyano
—S-ethyl
205
##STR00121##
methyl
trifluoro- methyl
cyano
—NH-ethyl
206
##STR00122##
methyl
trifluoro- methyl
cyano
—NH—OH
207
##STR00123##
methyl
trifluoro- methyl
cyano
—NH2
208
##STR00124##
methyl
trifluoro- methyl
cyano
—N(ethyl)2
209
##STR00125##
methyl
trifluoro- methyl
cyano
1-pyrrolidinyl
210
##STR00126##
methyl
trifluoro- methyl
cyano
—NH—O- methyl
211
##STR00127##
methyl
trifluoro- methyl
cyano
—NH-methyl
212
##STR00128##
methyl
trifluoro- methyl
cyano
—O-methyl
213
##STR00129##
methyl
chloro
chloro
—S-ethyl
214
##STR00130##
methyl
trifluoro- methyl
cyano
—NH—SO2- methyl
215
##STR00131##
(R)-methyl
trifluoro- methyl
cyano
—S-ethyl
216
##STR00132##
(S)-methyl
trifluoro- methyl
cyano
—S-ethyl
217
##STR00133##
(S)-methyl
trifluoro- methyl
cyano
—NH-cyano
218
##STR00134##
(S)-methyl
trifluoro- methyl
cyano
—S-ethyl
One skilled in the art will recognize that in the recitation of the substituent groups of
##STR00135##
the “●” symbol is intended to denote the point of attachment of the
##STR00136##
ring to the rest of the molecule.
One skilled in the art will further recognize that in the drawing of the substituent group
##STR00137##
in the compounds of formula (I) and compounds of formula (II), the “C” within the ring structure is intended to indicate a carbon atom. Thus when
##STR00138##
is other than phenyl, the
##STR00139##
ring is attached to the —(CH2)a— portion of the compounds of formula (I) through a carbon atom. One skilled in the art will further recognize that the
##STR00140##
substituent group further indicates the numbering of the atoms on the ring. More specifically, the “C” carbon atom is counted as 1, with the other atoms numbered (counted off) in a clockwise fashion. Thus for example, wherein the
##STR00141##
substituent group is other than phenyl, for example pyridyl, as in the following representative compound of formula (I)
##STR00142##
the
##STR00143##
substituent group is 3-pyridyl, substituted with a cyano group at the 4-position.
As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, the abbreviation “Ca-b” wherein a and b are integers, is intended to denote the number of carbon atoms within the substituent group. For example, C1-4alkyl denotes alkyl chains containing one (1) to four (4) carbon atoms. Similarly, C2-4alkenyl, denotes an alkenyl chain containing two (2) to four (4) carbon atoms.
As used herein, the term “alkyl” whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
As used herein, unless otherwise noted, the term “halogenated C1-4alkyl” shall mean any straight or branched alkyl chain comprising one to four carbon atoms wherein the alkyl chain is substituted with one or more, preferably one to five, more preferably one to three halogen atoms, and wherein the halogen atoms are independently selected from chloro, bromo, fluoro or iodo, preferably chloro or fluoro, more preferably fluoro. Suitable examples include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, and the like. Preferably, the halogenated C1-4alkyl is trifluoromethyl or 1-(2,2,2-trifluoroethyl), more preferably, trifluoromethyl.
As used herein, unless otherwise noted, the term “alkenyl” shall include straight and branched chains comprising at least one unsaturated double bond. Suitable examples include, but are not limited to, vinyl, 1-propenyl, and the like. Preferably, the alkenyl group contains one unsaturated double bond.
As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
As used herein, unless otherwise noted, the term “cycloalkyl” shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, unless otherwise noted, “heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
As used herein, the term “heterocycloalkyl” shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and the like.
As used herein, unless otherwise noted the term “5 or 6 membered, saturated, heterocyclic ring structure” shall mean any stable ring structure comprising 5 to 6 ring atoms independently selected from C, N, O and S, wherein the ring structure does not contain any unsaturated bonds. Preferably, the 5 to 6 membered, saturated heterocyclic ring structure contains one to two ring atoms selected from the group consisting of N, O and S (wherein the remaining ring atoms are C). More preferably, the 5 or 6 membered, saturated, heterocyclic ring structure contains one nitrogen ring atom and optionally contains an additional ring atom selected from the group consisting of O, N and S (wherein the remaining ring atoms are C). Suitable examples include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, and the like; preferably pyrrolidinyl.
As used herein, the notation “*” shall denote the presence of a stereogenic center.
When a particular group is “substituted” (e.g., alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
As used herein, unless otherwise noted, the term “aprotic solvent” shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2═CH—CH2—, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO2—R″ wherein R″ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC1-C6alkylaminocarbonylC1-C6alkyl” substituent refers to a group of the formula
##STR00144##
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edentate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following:
acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Compounds of formula (I) wherein
##STR00145##
is selected from
##STR00146##
may be prepared according to the process outlined in Scheme 1.
##STR00147##
Accordingly, a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XI), wherein Q1 is a suitable leaving group such as hydroxy, halogen, and the like, a known compound or compound prepared by known methods, according to known methods (for example, where Q is a halogen, in an organic solvent such as THF, methylene chloride, and the like; where Q is hydroxy, in the presence of cyanochloride, oxalyl chloride, and the like, in an organic solvent such as DMA, DMF, and the like), to yield the corresponding compound of formula (XII).
The compound of formula (XII) is reacted with a suitably substituted and protected hydrazone, a compound of formula (XIII), wherein R0 a group such as tolyl, and the like, (wherein —SO2—R0 is a leaving group), a known compound or compound prepared by known methods, in the presence of a base such as NaH, potassium t-butoxide, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux temperature, preferably at a temperature in the range of from about 80 to about 100° C., to yield the corresponding compound of formula (Ib).
The compound of formula (Ib) is further, optionally converted to the corresponding compound of formula (Ia) by treating the compound of formula (Ib) with a weak acid such as acetic acid, TFA, dilute HCl, and the like, or by passing the compound of formula (Ib) through silica gel, according to known methods.
The compound of formula (Ia) is further, optionally reacted with a suitably substituted alkylating agent, according to known methods, to yield the corresponding compound of formula (Ic).
One skilled in the art will recognize that compounds of formula (I) wherein
##STR00148##
and wherein R5′ is C1-4alkyl may be similarly prepared according to the process described in Scheme 1 by selecting and substituting a suitably substituted compound of formula (XXXX)
##STR00149##
for the compound of formula (XIII) above.
Compounds of formula (I) wherein
##STR00150##
and R5′ is halogen may be prepared from the corresponding compound of formula (I) wherein
##STR00151##
by reacting with a suitable source of the halogen (for example, wherein the halogen is chloro by reacting with PCl5 or POCl3) according to known methods.
Compounds of formula (I) wherein
##STR00152##
may be similarly prepared according to the process outlined in Scheme 1 above, by selecting and substituting a suitably substituted compound of formula (XXXXI)
##STR00153##
for the compound of formula (XIII).
Compounds of formula (I) wherein
##STR00154##
may be similarly prepared according to the process outlined in Scheme 1 above, by selecting and substituting a suitably substituted compound of formula (XXXXII)
##STR00155##
for the compound of formula (XIII).
Compounds of formula (Ic) wherein R10 is other than hydrogen may alternatively be prepared according to the process outline in Scheme 2.
##STR00156##
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted hydrazine, a compound of formula (XIV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 50° C., preferably at about room temperature, to yield the corresponding compound of formula (Ic).
Compounds of formula (I) wherein
##STR00157##
may be prepared according to the process outlined in Scheme 3.
##STR00158##
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 50° C., preferably at about room temperature, to yield the corresponding compound of formula (Id).
Compounds of formula (I) wherein
##STR00159##
may be prepared according to the process outlined in Scheme 4.
##STR00160##
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by known methods, in an organic solvent such as toluene, xylene, chlorobenzene, and the like, at a temperature in the range of about room temperature to about 120° C., to yield the corresponding compound of formula (Ie).
##STR00161##
Compounds of formula (I) wherein may be prepared according to the process outlined in Scheme 5.
##STR00162##
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitable reducing agent such as mCPBA, hydrogen peroxide, and the like, at a temperature in the range of about 0° C. to about room temperature, according to known methods, to yield the corresponding compound of formula (XVII).
The compound of formula (XVII) is reacted with a suitably substituted amine, a compound of formula (XVIII), a known compound or compound prepared by known methods, in an organic solvent such as DMF, DMSO, and the like, at a temperature in the range of about 0 to about 50° C., preferably at about room temperature, to yield the corresponding compound of formula (XIX).
The compound of formula (XIX) is reacted with a suitably substituted compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, and the like or in an alcohol such as methanol, ethanol, and the like, at a temperature in the range of about 0 to about 50° C., preferably at about room temperature, to yield the corresponding compound of formula (If).
Compounds of formula (I) wherein
##STR00163##
may be prepared according to the process outlined in Scheme 6.
##STR00164##
Accordingly, a suitably substituted compound of formula (XVII) is reacted with a suitably substituted compound of formula (XXI), a known compound or compound prepared by known methods, in the presence of a Lewis acid such as BF3● Etherate, AlCl3, and the like, in an organic solvent such as methylene chloride, chloroform, and the like, to yield the corresponding compound of formula (Ig).
Alternatively, a suitably substituted compound of formula (XlXa), a compound of formula (XIX) wherein R10 is hydrogen, is reacted with a suitably substituted compound of formula (XXII), wherein Q is a leaving group such as hydroxy, halogen, and the like, a known compound or compound prepared by known methods, according to known methods, at an elevated temperature in the range of from about 50 to about 120° C., preferably at an elevated temperature in the range of about 80 to about 120° C., to yield the corresponding compound of formula (Ig).
Compounds of formula (I) wherein
##STR00165##
may be prepared according to the process outlined in Scheme 7.
##STR00166##
Accordingly, a suitably substituted compound of formula (XXIII), wherein Q2 is suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, is reacted with a suitably substituted aldehyde, a compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, benzene, and the like, at a temperature in the range of from about room temperature to about 50° C., to yield the corresponding compound of formula (XXIV).
Wherein the compound of formula (XXIV) Q2 is alkoxy and the like, the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3Al, isopropyl-MgCl, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0° C. to about room temperature, to yield the corresponding compound of formula (Ih).
Alternatively, wherein the compound of formula (XXIV) Q2 is hydroxy, the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50° C., to yield the corresponding compound of formula (Ih).
Compounds of formula (I) wherein
##STR00167##
may be prepared according to the process outlined in Scheme 8.
##STR00168##
Accordingly, a suitably substituted compound of formula (XXV), wherein Q3 is a suitable leaving group such as hydroxy, halogen, alkoxy, and the like, is reacted with 1,1′carbonyl-diimidazole (CDI), in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, to yield the corresponding compound of formula (XXVI).
Wherein the compound of formula (XXVI) Q3 is alkoxy and the like, the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3Al, isopropyl-MgCl, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0° C. to about room temperature, to yield the corresponding compound of formula (Ij).
Alternatively, wherein the compound of formula (XXVI) Q3 is hydroxy, the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50° C., to yield the corresponding compound of formula (Ij).
Compounds of formula (I) wherein
##STR00169##
may be prepared according to the process outlined in Scheme 9.
##STR00170##
Accordingly, a suitably substituted compound of formula (XXVII), wherein Q4 is a suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXVIII), wherein Q5 is a suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as THF, toluene, benzene, and the like, at a temperature in the range of from about 50 to about 80° C., to yield the corresponding compound of formula (XXIX).
Wherein the compound of formula (XXIX) Q4 is alkoxy and the like, the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3Al, isopropyl-MgCl, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0° C. to about room temperature, to yield the corresponding compound of formula (Ik).
Alternatively, wherein the compound of formula (XXIX) Q4 is hydroxy, the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50° C., to yield the corresponding compound of formula (Ik).
Compounds of formula (I) wherein
##STR00171##
may be prepared according to the process outlined in Scheme 10.
##STR00172##
Accordingly, a suitably substituted compound of formula (Im), a compound of formula (Ic) wherein R5 is hydrogen, is reacted with a reducing agent such as NaBH4, NaCNBH3, and the like, in an organic solvent such as AcOH, CF3CO2H, methanol, and the like, at a temperature in the range of from about 0° C. to about room temperature, to yield the corresponding compound of formula (In).
The compound of formula (In) is reacted with a suitably substituted compound of formula (XXX), wherein Q6 is a suitable leaving group such as halogen, alkyl-carbonyl-oxy-, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, DMF, and the like, at a temperature in the range of from about 0° C. to about room temperature, to yield the corresponding compound of formula (Ip).
Compounds of formula (I) wherein W is S, may be prepared according to the process outlined in Scheme 11.
##STR00173##
Accordingly, a suitably substituted compound of formula (Ix) is reacted with a source of sulfur such as Lawesson's reagent, P2S5, and the like, in an organic solvent such as toluene, xylene, p-oxlane, and the like, at a temperature in the range of from about 110° C. to about 150° C., to yield the corresponding compound of formula (Iy).
Compounds of formula (II) wherein Q is —ORE may be prepared according to the process outlined in Scheme 12.
##STR00174##
Accordingly, a suitably substituted compound of formula (Ix) wherein R2 is hydrogen, is recated with a suitably substituted electrophile, a compound of formula (XXXI) wherein LV is a suitable leaving group such as Cl, Br, tosyl, triyl, mesyl, and the like, (for example where RE is ethyl, the compound of formula (XXIX) may be BF4 etherate), in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, diethyl ether, and the like, at a temperature in the range of from about −40° C. to about room temperature, to yield a mixture of the corresponding compound of formula (IIa) and (Iz).
Compounds of formula (II) wherein Q is —SRE or —N(RF)2 may be prepared according to the process outlined in Scheme 13.
##STR00175##
Accordingly, a suitably substituted compound of formula (Iy) is reacted with a suitably substituted compound of formula (XXXI), wherein LV is a suitable leaving group such as Cl, Br, tosyl, trifyl, mesyl, and the like, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as acetone, THF, DMF, and the like, at a temperature in the range of from about 0° C. to about 80° C., to yield the corresponding compound of formula (IIb).
The compound of formula (IIb) is reacted with a suitably substituted nitrogen containing nucleophile, a compound of formula (XXXII) (for example, NH3, NH(C1-4alkyl), N(C1-4alkyl)2, NH(OC1-4alkyl), NH2(OH), NH(CN), NH(SO2—C1-4alkyl), pyrrolidine, and the like), in the presence of an inorganic base such as K2CO3, NaH, Na2CO3, and the like, in an organic solvent such as THF, DMF, dioxane, and the like, at a temperature in the range of from about room temperature to about 100° C., to yield the corresponding compound of formula (IIc).
One skilled in the art will recognize that when in the compound of formula (IIc) at least one RF group is hydrogen, then the corresponding compound of formula (I) wherein W is NHRF is its tautomer.
One skilled in the art will recognize that compound of formula (I) wherein
##STR00176##
is other than phenyl, may be similarly prepared according to the processes outlined in Scheme 1-9 above, by selecting and substituting suitably substituted compounds for the starting materials and reagents.
One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and/or (II) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 50-100 mg and may be given at a dosage of from about 0.5-5.0 mg/kg/day, preferably from about 1.0-3.0 mg/kg/day. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating a disorder mediated by one or more androgen receptor(s) described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 500 mg, preferably about 50 to 100 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by one or more androgen receptor(s) is required.
The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is from about 0.5 to about 5.0 mg/kg of body weight per day, most preferably, from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products may be listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
One skilled in the art will recognize that in the Examples which follow and describe the preparation of compounds of formula (II) wherein Z is NHRF and their corresponding tautomers (compounds of formula (I) wherein W is NRF), the identity and ratio of the two tautomeric forms in the isolated product was not determined.
##STR00177##
Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated with thionyl chloride (714 mg, 6 mmol) at 0° C. The mixture was stirred for 30 min then 4-cyano-3-trifluoromethyl-aniline (1.0 g, 6.0 mmol) was added. The resulting suspension was stirred overnight and then quenched with NaHCO3. The reaction mixture was extracted with ethyl acetate, washed with brine and dried with Na2SO4. The resulting concentrated crude product was purified on column (Ethyl acetate:Hexane, 1:2) to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 8.10 (s, 1H), 7.95 (dd, J=1.5 Hz, 0.5 Hz, 1H), 7.90 (br, 1H), 7.75 (d, J=1.5 Hz), 5.85 (s, 1H), 5.60 (s, 1H), 2.10 (s, 3H).
MS (m/z): M+Na (277).
##STR00178##
Following the procedure described in Example 1, starting from 4-nitro-3-trifluoromethyl-aniline (2.06 g, 10.0 mmol), the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 8.00 (m, 3H), 7.95 (s, 1H), 5.88 (s, 1H), 5.60 (s, 1H), 2.10 (s, 3H).
MS (m/z): M+Na (297)
##STR00179##
Following the procedure described in Example 1, starting from 4-chloro-3-trifluoromethyl-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.90 (s, 1H), 7.70 (dd, J=1.5 Hz, 0.5 Hz, 1H), 7.40 (d, J=1.5 Hz), 5.80 (s, 1H), 5.50 (s, 1H), 2.00 (s, 3H).
MS (m/z): MH+ (263)
##STR00180##
Following the procedure described in Example 1, starting from 4-bromo-3-trifluoromethyl-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.90 (s, 1H), 7.85 (s, br, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 2.08 (s, 3H)
##STR00181##
Following the procedure described in Example 1, starting from 3,4-di-chloro-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.85 (s, 1H), 7.50 (s, br, 1H), 7.36 (s, 2H), 5.78 (s, 1H), 5.51 (s, 1H), 2.08 (s, 3H).
MS (m/z): MH+ (230).
##STR00182##
Following the procedure described in Example 1, starting from 3,4-di-cyano-aniline the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 8.25 (s, 1H), 8.05 (s, br, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 5.88 (s, 1H), 5.65 (s, 1H), 2.11 (s, 3H)
MS (m/z): MNa+ (234)
##STR00183##
Following the procedure described in Example 1, starting from (4-amino-phenyl)-phenyl-methanone, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.98 (s, br, 1H), 7.88˜7.72 (m, 6H), 7.60 (t, J=8.5 Hz, 1H), 7.52 (t, J=7.8 Hz, 2H), 5.88 (s, 1H), 5.55 (s, 1H)
MS (m/z): MH+ (266), MNa+ (288)
##STR00184##
Following the procedure described in Example 1, starting from (4-Aminomethyl-phenyl)-phenyl-methanone, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.38˜7.22 (m, 4H), 7.10 (t, J=7.5 Hz, 1H), 7.00 (m, 4H), 6.15 (s, br, 1H), 5.71 (s, 1H), 5.35 (s, 1H), 4.52 (d, J=4.5 Hz, 2H), 2.11 (s, 3H)
MS (m/z): MH+ (280), MNa+ (302)
##STR00185##
Following the procedure described in Example 1, starting from 4-phenoxy-phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.70 (s, 1H), 7.50 (m, 2H), 7.30 (m, 2H), 7.00 (m, 5H), 5.80 (s, 1H), 4.90 (s, 1H), 2.00 (s, 3H). MS (m/z): M+1 (254).
MS (m/z): MH+ (254), MNa+ (276)
##STR00186##
Following the procedure described in Example 1, starting from 4-cyano-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.70 (m, 5H), 5.80 (s, 1H), 5.05 (s, 1H), 2.00 (s, 3H)
MS (m/z): MH+ (187), MNa+ (209)
##STR00187##
Following the procedure described in Example 1, starting from 4-phenylsulfanyl-phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.60 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.20 (m, 5H), 5.80 (s, 1H), 5.00 (s, 1H), 2.00 (s, 3H)
MS (m/z): MH+ (270), MNa+ (292)
##STR00188##
Following the procedure described in Example 1, starting from 4-benzyl-phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 8.00 (d, J=9.0 Hz, 1H), 7.15-7.35 (m, 9H), 5.35 (s, 1H), 5.25 (s, 1H), 1.75 (s, 3H)
MS (m/z): MH+ (252), MNa+ (274)
##STR00189##
Following the procedure described in Example 1, starting from 4-methanesulfonyl-benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.75 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 6.92 (s, 1H), 5.78 (s, 1H), 5.38 (s, 1H), 4.55 (d, J=6.5 Hz, 2H), 3.02 (s, 3H), 2.05 (s, 3H)
MS (m/z): MH+ (254), MNa+ (276)
##STR00190##
Following the procedure described in Example 1, starting from 4-chloro-benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.20 (m, 4H), 6.15 (s, 1H), 5.75 (s, 1H), 4.85 (s, 1H), 4.50 (d, J=5.0 Hz, 2H), 2.00 (s, 3H).
MS (m/z): MH+ (210).
##STR00191##
Following the procedure described in Example 1, starting from 4-phenoxy-benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 7.18˜6.94 (m, 4H), 6.85 (t, J=6.5 Hz, 1H), 6.77 (m, 4H), 5.56 (s, br, 1H), 5.65 (s, 1H), 5.30 (s, 1H), 4.38 (d, J=5.5 Hz, 2H), 2.06 (s, 3H)
MS (m/z): MH+ (268), MNa+ (290)
##STR00192##
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-ethyl-acrylic acid, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 8.70 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=12.0H, 1H), 7.78 (d, J=12.0 Hz, 1H), 5.75 (s, 1H), 5.05 (s, 1H), 2.40 (q, J=9.0 Hz, 2H), 1.11 (t, J=9.0 Hz, 3H).
MS (m/z): MH+ (270), MNa+ (292)
##STR00193##
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-propyl-acrylic acid, the title compound was prepared as a yellow solid.
MS (m/z): MH+ (284), MNa+ (306).
1H NMR (CDCl3) δ 8.20 (s, 1H), 8.12 (s, 1H), 8.00 (d, J=12.0 Hz, 1H), 7.78 (d, J=12.0 Hz, 1H), 5.70 (s, 1H), 5.00 (s, 1H), 2.40 (t, J=9.0 Hz, 2H), 1.50 (m, 2H), 0.95 (t, J=9.0 Hz, 3H).
##STR00194##
4-Fluorobenzenealdehyde (1.24 g, 10.0 mmol) in benzene (40 ml) was mixed with benzyl hydrazine hydrochloride (1.95 g, 10.0 mmol). The reaction was stirred at room temperature for 12 h. The solvent was then removed by vacuum evaporation to yield the title compound as a white solid.
1H NMR (CDCl3) δ 7.60 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 4.45 (s, 1H).
MS (m/z): MH+ (227)
##STR00195##
Following the procedure described in Example 18, starting from N-(4-formyl-phenyl)-acetamide and methyl hydrazine, the title compound was prepared as a white solid.
##STR00196##
Following the procedure described in Example 18, starting from N-(4-formyl-phenyl)-acetamide and N-hydroxyamine, the title compound was prepared as a white solid.
MS (m/z): MH+ (140).
##STR00197##
NCS (1.33 g, 10.0 mmol) was mixed with dimethyl sulfide (620 mg, 10.0 mmol) in CH2Cl2 (20 ml) at 0° C. for 30 min. The mixture was then cooled to −78° C. and N-benzyl-N″-(4-fluoro-benzylidene)-hydrazine, prepared as in Example 19, (2.62 g, 10.0 mmol) was added into the mixture. The mixture was maintained at −78° C. for 1 h, then slowly warmed up to room temperature over 2 hrs. The reaction mixture was quenched by NaHCO3, then extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (100% CH2Cl2, Rf=0.5) yielded the title compound as a white solid.
1H NMR (CDCl3) δ 7.80 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 6.10 (br, 1H).
MS (m/z): MH+ (260).
##STR00198##
Following the procedure described in Example 21, starting from N-[4-(methyl-hydrazonomethyl)-phenyl]-acetamide, the title compound was prepared as a white solid.
MS (m/z): MH+ (226).
##STR00199##
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (500 mg, 2.0 mmol) was mixed with 4-fluoro-N-(phenylmethyl)-benzenecarbohydrazonoyl chloride (520 mg, 2.0 mmol) in CH2Cl2 at room temperature. Triethyl amine (300 mg, 3.0 mmol) was then added to the reaction mixture. The reaction was refluxed overnight, then quenched with NaHCO3, and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (Hexane:ethyl acetate, 5:1, Rf=0.5) yielded the title compound as a white solid.
1H NMR (CDCl3) δ 9.25 (s, 1H), 7.80 (s, 1H), 7.70 (s, 2H), 7.60 (m, 2H), 7.45 (m, 2H), 7.05 (m, 5H), 4.30 (dd, J=11.1 Hz, 1.0 Hz, 2H), 3.30 (dd, J=3.6 Hz, 1.2 Hz, 2H), 1.65 (s, 3H).
MS (m/z): MH+ (481)
##STR00200##
2-Benzyl-5-(4-fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (150 mg, 0.33 mmol) in ethanol, was treated with Pd/C (100 mg, 10%) under H2 balloon for two days. Pd/C was removed by vacuum filtration and the solvent was removed by vacuum rotary evaporation to yield a crude product. Purification of the crude product by silica gel (Hex:ethyl acetate, 2:1, Rf=0.4) yielded the title compound as a white solid.
1H NMR (CDCl3) δ 9.75 (s, 1H), 8.10 (s, 1H), 7.85 (dd, J=4.5 Hz, 0.2 Hz, 2H), 7.65 (m, 2H), 7.05 (m, 2H), 5.70 (br, 1H), 3.30 (dd, J=3.6 Hz, 1.2 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ (390)
##STR00201##
Following the procedure described in Example 23, starting from 2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide and 4-acetamido-N-(methyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as a white solid.
1H NMR (CDCl3) δ 9.62 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 7.50 (m, 4H), 3.38 (abq, J=12.5 Hz, 2H), 2.98 (s, 3H), 2.20 (s, 3H), 1.50 (s, 3H).
MS (m/z): MH+ (444), MH− (442)
##STR00202##
Following the procedure described in Example 23, starting from 2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and 4-acetamido-N-(methyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as a white solid.
1H NMR (CDCl3) δ 9.52 (s, 1H), 8.15 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.55 (m, 4H), 3.38 (abq, J=12.5 Hz, 2H), 2.98 (s, 3H), 2.18 (s, 3H), 1.48 (s, 3H)
MS (m/z): MH+ (464), MNa+ (486)
##STR00203##
4-Fluorobenzamidoxime (1.39 g, 10 mmol) was mixed with triethylamine (200 mg, 2.0 mmol) and NaOCl (4%, 15 ml, 1.48 g, 10 mmol) in CH2Cl2 (25 ml). N-(4-(Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (508 mg, 2.0 mmol) was added into the mixture and the mixture was then stirred for 3 hrs at room temperature. The reaction mixture was quenched by NaHCO3, and then extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (Hexane:ethyl acetate, 2:1, Rf=0.45) yielded the title compound as a white solid.
1H NMR (CDCl3) δ 9.15 (s, 1H), 8.15 (s, 1H), 7.85 (dd, J=4.5 Hz, 0.2 Hz, 2H), 7.60 (m, 2H), 7.05 (m, 2H), 3.75 (dd, J=17.4 Hz, 2.0 Hz, 2H), 1.75 (s, 3H).
MS (m/z): MH+ (392)
##STR00204##
p-Toluenesulfonylhydrazine (10.0 mmol) was mixed with a suitably selected compound of the formula R—CHO (10.0 mmoL) in methanol (40 ml) at room temperature for 4 h. The mixture was then concentrated to yield the title compound as a white solid (unless otherwise noted).
##STR00205##
2-[(1E)-(4-fluorophenyl)methylidene]toluenesulfonylhydrazone, prepared according to the procedure described in Example 29 (600 mg, 2.1 mmol) in THF (20 ml) was treated by NaH (60%, 120 mg, 3 mmol) at 0° C. for 20 min, followed by the addition of N-(4-cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (500 mg, 2.0 mmol). The reaction mixture was then heated to 55° C. overnight, then quenched by NaHCO3, and extracted by ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield crude product as a mixture. Purification of the crude product on a column yielded the title compound as separate products, as a white solids.
(Hexane:ethyl acetate, 2:1, Rf=0.45, 475 mg, 61%)
(Hexane:ethyl acetate: 2:1, Rf=0.6, 100 mg, 13%):
MS (m/z): MH+ (391)
1H NMR (CDCl3) δ 8.50 (s, 1H), 8.10 (s, 1H), 7.90 (dd, J=1.5 Hz, 0.2 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.20 (m, 2H), 7.10 (m, 2H), 5.60 (t, J=0.9 Hz, 1H), 3.00 (dd, J=1.0 Hz, 0.8 Hz, 1H), 1.87 (s, 3H), 1.55 (t, J=1.1 Hz, 0.6 Hz, 1H).
##STR00206##
Following the procedure described in Example 29, starting from 2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and 2-[(1E)-(4-fluorophenyl)methylidene]toluenesulfonylhydrazone, the title compound was prepared as a yellow solid.
1H NMR (MeOH) δ 6.45 (d, J=0.9 Hz, 1H), 6.20 (m, 1H), 6.00 (s, 1H), 5.55 (m, 4H), 2.00 (dd, J=5.5 Hz, 1.8 Hz, 2H), 1.70 (s, 3H).
MS (m/z): MNa+ (410)
##STR00207##
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (180 mg, 0.71 mmoL) in THF (5 mL) was treated with TMSCHN2 (2.0 M in hexanes, 3.54 mmoL, 1.8 mL) at −10° C. The reaction mixture was then warmed to room temperature slowly and stirred overnight. The solvent was removed and the residue was purified by column chromatography (silica gel, 1:1 hexanes:EtOAc) to yield the title compound as a white solids (1:1 diastereomers).
1H NMR (CDCl3) δ 8.58 (br, s, 1H) for diastereomer 1, 8.35 (br, s, 1H) for diastereomer 2, 7.90 (m, 1), 7.70 (m, 1H), 7.58 (m, 1H), 4.35 (dd, J=10.5, 5.0 Hz, 1H) for diastereomer 1, 4.30 (dd, J=11.0, 6.0 Hz, 1H) for diastereomer 2, 2.30 (m, 1H) for diastereomer 1, 2.05 (m, 1H) for diastereomer 2, 1.66 (m, 1H) for diastereomer 1, 1.48 (s, 3H) for diastereomer 1, 1.42 (s, 3H) for diastereomer 2, 1.29 (m, 1H) for diastereomer 2), 0.10 (s, 9H) for diastereomer 1), 0.01 (s, 9H) for diastereomer 2
MS (m/z), 298 [M-TMS+H]+, 319 [M-TMS+Na]+
1H NMR (CDCl3) 9.62 (s, 1H), 8.10 (s, 1H), 7.95 (d, J=6.5 Hz, 1H), 7.77 (d, J=6.5 Hz, 1H), 6.88 (s, 1H), 5.52 (s, 1H), 3.05 (abq, J=12.5 Hz, 2H), 1.56 (s, 3H)
MS (m/z), MH+ (297).
##STR00208##
Following the procedure described in Example 31, starting from 2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and TMSCHN2 the title compounds were prepared, both as a white solids.
1H NMR (CDCl3) δ 9.62 (br, s, 1H), 8.10 (s, 1H), 7.98 (m, 2H), 6.88 (s, 1H), 5.50 (s, 1H), 3.10 (Abq, J=12.5 Hz, 2H), 1.52 (s, 3H)
MS (m/z), MH+, 317, MH−, 315
1H NMR (CDCl3) δ 8.78 (br, s, 1H), 8.05 (s, 1H), 7.88 (d, J=7.0 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 4.48 (dd, J=11.0, 4.5 Hz, 1H), 2.10 (dd, J=13.0, 11.0 Hz, 1H), 1.78 (dd, J=13.0, 4.5 Hz, 1H), 1.55 (s, 3H)
##STR00209##
Following the procedure described in Example 29, 4-methyl-2-[(1Z)-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.25 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.65 (d, J=0.6 Hz, 1H), 7.10 (m, 1H), 6.80 (m, 3H), 5.80 (m, 1H), 2.30 (m, 1H), 1.80 (m, 1H), 1.51 (s, 3H), 0.89 (s, 9H), 0.21 (s, 6H)
MS (m/z): M+(503)
##STR00210##
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamide, prepared as in Example 34 (80 mg, 1.6 mmol) in THF (20 ml) was treated with TBAF (1M, 3.2 ml, 3.2 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h, then quenched with H2O, extracted with ethyl acetate, dried over Na2SO4 and concentrated to yield a crude product. The crude product was purified by silica gel (Hexane:ethyl acetate, 2:1, Rf=0.35) to yield the title compound as a white solid.
1H NMR (CDCl3) δ10.78 (br, 1H), 9.75 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.70 (d, J=0.6 Hz, 1H), 7.25 (m, 1H), 7.08 (d, J=0.6 Hz, 1H), 6.85 (m, 1H), 5.95 (s, 1H), 3.40 (dd, J=5.1 Hz, 2.1 Hz, 1H), 1.65 (s, 3H)
MS (m/z): MNa+ (401)
1H NMR (CDCl3) δ 9.80 (s, 1H), 8.25 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J=6.6 Hz, 2H), 6.92 (d, J=6.6 Hz, 2H), 5.70 (br, 1H), 3.15 (abq, J=12.5 Hz, 1H), 1.55 (s, 3H)
MS (m/z): MNa+ (401)
##STR00211##
Following the procedure described in Example 29, 4-methyl-2-[(1Z)-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-fluorophenyl]methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.65 (d, J=0.6 Hz, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 6.75 (m, 1H), 5.50 (br, 1H), 3.25 (dd, J=5.1 Hz 1.2 Hz, 2H), 1.55 (s, 3H), 0.78 (s, 9H), 0.21 (d, J=4.8 Hz, 6H)
MS (m/z): M Na+ (544), M− (520)
##STR00212##
Following the procedure described in Example 34, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-fluorophenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamide, prepared as in Example 36, was reacted to yield the title compound as a white solid.
MS (m/z): M+ (407)
1H NMR (CDCl3) δ10.84 (s, 1H), 9.63 (s, 1H), 8.14 (s, 1H), 7.97 (d, J=0.6 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 7.11 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 5.87 (s, 1H), 3.45 (dd, J=3.6 Hz, 1.2 Hz, 2H), 1.69 (s, 3H)
##STR00213##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2-thienylmethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.75 (s, 1H), 8.13 (s, 1H), 7.92 (dd, J=1.1 Hz, 0.2 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.37 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 5.55 (br, 1H), 3.35 (dd, J=5.4 Hz, 1.7 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ (379)
##STR00214##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2-furanylmethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.75 (s, 1H), 8.13 (s, 1H), 7.92 (dd, J=1.1 Hz, 0.2 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 6.65-6.50 (m, 3H), 3.31 (dd, J=5.4 Hz, 1.7 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ (363)
##STR00215##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-(tetrahydro-2-furanyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.09 (s, 1H), 8.16 (m, 1H), 7.95 (m, 1H), 7.81 (d, J=0.6 Hz, 1H), 4.49 (dd, J=1.0 Hz, 0.5 Hz, 1H), 4.00-3.60 (m, 3H), 2.50-1.60 (m, 6H), 1.56 (s, 3H)
MS (m/z): MH+ (366)
##STR00216##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.30 (s, 1H), 8.11 (s, 1H), 7.98 (dd, J=1.1 Hz, 0.2 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 6.18 (br, 1H), 3.15 (dd, J=6.0 Hz, 1.8 Hz, 2 H), 1.62 (s, 3H)
MS (m/z): MNa+ (387)
##STR00217##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-cyclohexylmethylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
(Hexane:Ethyl Acetate, 2:1, Rf=0.2, 210 Mg, 19%)
1H NMR (CDCl3) δ 9.82 (s, 1H), 8.10 (s, 1H), 7.95 (dd, J=1.0 Hz, 0.2 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 2.98 (dd, J=5.1 Hz, 1.7 Hz, 2H), 1.77 (m, 6H), 1.50 (s, 3H), 1.27 (m, 4H).
MS (m/z): MH+ (379)
(Hexane:Ethyl Acetate, 2:1, Rf=0.8, 160 Mg, 16%)
1H NMR (CDCl3) δ 9.20 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J=1.0 Hz, 0.2 Hz, 1H), 7.85 (d, J=0.9 Hz, 1H), 4.36 (dd, J=1.5 Hz, 0.8 Hz, 1H), 2.15 (d, J=1.0 Hz, 1H), 1.70 (m, 6H), 1.55 (s, 3H), 1.20 (m, 5H)
MS (m/z): MNa+ (401)
##STR00218##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-(4-ethylphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.80 (s, 1H), 8.16 (m, 1H), 7.90 (d, J=0.6 Hz, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.50 (d, J=0.8 Hz, 2H), 7.15 (d, J=0.8 Hz, 2H), 5.83 (br, 1H), 3.32 (dd, J=3.9 Hz, 1.3 Hz, 1H), 2.65 (q, J=0.6 Hz, 2H), 1.62 (s, 3H), 1.20 (t, J=0.4 Hz, 3H)
MS (m/z): MH+ (401)
##STR00219##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-(4-fluoro-3-methylphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.75 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.50-7.40 (m, 2H), 7.05 (m, 2H), 4.60 (br, 1H), 3.30 (dd, J=3.9 Hz, 1.3 Hz, 1H), 2.30 (s, 3H), 1.65 (s, 3H)
MS (m/z): MNa+ (427)
##STR00220##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2-methylpropylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
(Hexane:Ethyl Acetate, 2:1, Rf=0.2, 350 Mg, 35%)
1H NMR (CDCl3) δ 9.85 (s, 1H), 8.10 (s, 1H), 7.95 (dd, J=1.0 Hz, 0.2 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 5.35 (br, 1H), 2.98 (dd, J=5.4 Hz, 1.8 Hz, 2H), 1.55 (s, 3H), 1.16 (s, 3H), 1.17 (s, 3H)
MS (m/z): MH+ (339)
(Hexane:Ethyl Acetate, 2:1, Rf=0.8, 560 Mg, 55%)
1H NMR (CDCl3) δ 9.18 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J=1.0 Hz, 0.2 Hz, 1H), 7.85 (d, J=0.9 Hz, 1H), 4.36 (dd, J=1.2 Hz, 0.6 Hz, 1H), 2.16 (q, J=0.7 Hz, 1H), 1.80 (m, 2H), 1.55 (s, 3H), 1.22 (d, J=0.7 Hz, 3H), 1.00 (d, J=0.7 Hz, 3H)
MS (m/z): M+ (338)
##STR00221##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-(4-methoxyphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.85 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.76 (d, J=0.6 Hz, 1H), 7.58 (d, J=0.6 Hz, 2H), 6.90 (d, J=0.6 Hz, 2H), 5.68 (br, 1H), 3.82 (s, 3H), 3.30 (dd, J=3.9 Hz, 1.3 Hz, 1H), 1.65 (s, 3H)
MS (m/z): M+ (403)
##STR00222##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-(pentafluorophenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.53 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=0.6 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 6.27 (s, 1H), 3.40 (dd, J=6.0 Hz, 1.8 Hz, 1H), 1.67 (s, 3H)
MS (m/z): M+ (463)
##STR00223##
Diazoethane (˜0.5 M, 20 mL) in diethyl ether (which may be prepared by according to known methods) was added into 2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (250 mg, 1 mmoL) in THF (2 mL) at room temperature. The solution was stirred at room temperature for 72 hours. The solvent was removed and the residue was purified by column chromatography to yield the title compounds as a white solids.
1H NMR (CDCl3) δ 9.06 (s, 1H), 8.16 (s, 1H), 7.99 (d, J=0.6 Hz, 1H), 7.82 (d, J=0.6 Hz, 1H), 4.58 (m, 1H), 2.06 (dd, J=1.3 Hz, 0.5 Hz, 1H), 1.59 (m, 1H), 1.56 (s, 3H)
MS (m/z): MNa+ (333)
1H NMR (CDCl3) δ 9.85 (s, br, 1H0, 8.05 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 2.95 (abq, J=12.5 Hz, 2H), 1.98 (s, 3H), 1.55 (s, 3H)
MS (m/z): MH+ (311), MH− (309).
##STR00224##
Following the procedure described in Example 29, the mixture of 4-methyl-2-[(1E)-propylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
(Hexane:Ethyl Acetate, 2:1, Rf=0.30)
1H NMR (CDCl3) δ 9.09 (s, 1H), 8.18 (s, 1H), 8.00 (d, J=0.6 Hz, 1H), 7.98 (d, J=0.6 Hz, 1H), 4.48 (m, 1H), 2.10 (m, 2H), 2.00 (m, 1H), 1.65 (m, 1H), 1.56 (s, 3H), 1.01 (t, J=0.7 Hz, 3H)
MS (m/z): MNa+ (347)
(Hexane:Ethyl Acetate, 2:1, Rf=0.10)
1H NMR (CDCl3) δ 9.89 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.80 (d, J=0.6 Hz, 1H), 5.33 (m, 1H), 2.95 (dd, J=6.0 Hz, 1.4 Hz, 2H), 2.35 (q, J=0.6 Hz, 2H), 1.58 (s, 3H), 1.18 (t, J=0.6 Hz, 3H)
MS (m/z): MNa+ (347)
##STR00225##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-3-methylbutylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
(Hexane:Ethyl Acetate, 2:1, Rf=0.80)
1H NMR (CDCl3) δ 9.10 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=0.6 Hz, 1H), 7.82 (d, J=0.6 Hz, 1H), 4.55 (q, J=0.5 Hz, 1H), 2.00 (m, 3H), 1.60 (m, 1H), 1.57 (s, 3H), 1.39 (m, 1H), 1.04 (t, J=0.5 Hz, 3H)
MS (m/z): MNa+ (375)
(Hexane:Ethyl Acetate, 2:1, Rf=0.20)
1H NMR (CDCl3) δ 9.86 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=0.6 Hz, 1H), 7.77 (d, J=0.6 Hz, 1H), 5.39 (br, 1H), 2.90 (dd, J=5.4 Hz, 1.3 Hz, 2H), 2.19 (d, J=0.5 Hz, 2H), 1.91 (m, 1H), 1.57 (s, 3H), 0.93 (m, 6H)
MS (m/z): M+ (353)
##STR00226##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-3-(methylthio)propylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.02 (s, 1H), 8.15 (s, 1H), 7.98 (d, J=0.6 Hz, 1H), 7.82 (d, J=0.6 Hz, 1H), 4.71 (q, J=0.5 Hz, 1H), 2.82 (m, 2H), 2.35 (m, 1H), 2.11 (s, 3H), 2.08 (m, 1H), 1.95 (m, 1H), 1.60 (m, 1H), 1.57 (s, 3H)
MS (m/z): MNa+ (393).
##STR00227##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-butylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
(Hexane:Ethyl Acetate, 2:1, Rf=0.70)
1H NMR (CDCl3) δ 9.11 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=0.6 Hz, 1H), 7.70 (d, J=0.6 Hz, 1H), 4.42 (q, J=0.5 Hz, 1H), 2.00 (m, 3H), 1.60 (m, 3H), 1.49 (s, 3H), 1.00 (t, J=0.5 Hz, 3H)
MS (m/z): M+ (338)
(Hexane:Ethyl Acetate, 2:1, Rf=0.15)
1H NMR (CDCl3) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 5.39 (s, 1H), 2.90 (dd, J=5.8, 1.2 Hz, 2H), 2.29 (t, J=0.6 Hz, 2H), 1.57 (m, 2H), 1.56 (s, 3H), 0.95 (t, J=0.5 Hz, 3H)
MS (m/z): M+ (338).
##STR00228##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-4-(acetamidophenyl)methylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.70 (s, 1H), 8.11 (s, 1H), 7.93-7.79 (m, 2H), 7.55 (s, 4H), 5.65 (s, 1H), 3.82 (dd, J=4.8, 2.4 Hz, 2H), 2.20 (s, 3H), 2.00 (s, 3H).
MS (m/z): M+ (430)
##STR00229##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-4-(acetamidophenyl)methylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 8.30 (s, 1H), 8.15-8.01 (m, 2H), 7.58 (m, 4H), 3.82 (dd, J=7.5, 2.4 Hz, 2H), 2.05 (s, 3H), 2.00 (s, 3H).
MS (m/z): M+ (450), M− (448)
##STR00230##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4-cyano-phenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 9.05 (s, 1H), 7.70-7.60 (m, 4H), 5.95 (s, 1H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).
MS (m/z): M− (295)
##STR00231##
Following the procedure described Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4-cyano-3-chloro-phenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 8.95 (s, 1H), 7.95 (s, 1H), 7.75 (m, 1H), 7.50 (m, 1H), 6.00 (s, 1H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (374)
##STR00232##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(3,4-dichlorophenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 8.85 (s, 1H), 7.85 (s, 1H), 7.40 (m, 2H), 5.85 (s, 1H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (341).
##STR00233##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with N-(4-Benzyl-phenyl)-2-methyl-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 8.60 (s, 1H), 8.00 (m, 1H), 7.30-7.10 (m, 8H), 5.40 (s, 1H), 4.00 (s, 2H), 2.70 (s, 2H), 1.38 (s, 3H).
MS (m/z): MH+ (362)
##STR00234##
Following the procedure described in Example 29, 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with N-(4-benzoyl-phenyl)-2-methyl-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ 9.00 (s, 1H), 7.85 (m, 2H), 7.75 (m, 2H), 7.58 (m, 5H), 5.90 (s, 1H), 3.15 (dd, J=6.5, 2.1 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (376)
##STR00235##
Following the procedure described in Example 29, the title compound was prepared as a white solid.
1H NMR (CDCl3) δ 8.75 (s, 1H), 7.55 (m, 2H), 7.30 (m, 2H), 7.10 (m, 5H), 5.75 (s, 1H), 3.15 (dd, J=6.4, 2.1 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (364).
##STR00236##
Following the procedure described Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.37 (s, 1H), 8.11 (s, 1H), 7.95-7.80 (m, 2H), 6.10 (s, 1H), 3.22 (dd, J=6.0, 2.7 Hz, 2H), 2.05 (m, 2H), 1.00 (t, J=1.5 Hz, 3H).
MS (m/z): MH+ (379).
##STR00237##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.30 (s, 1H), 8.15 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 6.25 (s, 1H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 2.00 (m, 2H), 1.30 (m, 2H), 1.65 (t, J=1.0 Hz, 3H)
MS (m/z): MH+ (393).
##STR00238##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 7.90 (m, 2H), 7.45 (m, 2H), 6.75 (s, 1H), 4.50 (m, 2H), 3.05 (s, 3H), 3.00 (dd, J=6.0, 2.7 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (364).
##STR00239##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.75 (s, 1H), 7.55 (m, 2H), 7.35 (m, 2H), 7.23 (m, 5H), 5.70 (s, 1H), 3.00 (dd, J=8.4, 2.4 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (380)
##STR00240##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-phenylsulfanyl-phenyl)-amide (100 mg, 0.264 mmoL) in EtOAc (2 mL) at room temperature was treated with Oxone (1.0 g) in water (10 mL). Sat. NaHCO3 was added to adjust pH 7˜8. The reaction mixture was stirred for 2 hrs. The mixture was then partitioned between ethyl acetate and water. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using ethyl acetate as eluent to afford the title product.
1H NMR (CDCl3) δ 8.50 (s, 1H), 7.55 (m, 4H), 7.45 (m, 5H), 2.90 (dd, J=6.4, 2.1 Hz, 2H), 1.80 (s, 3H).
MS (m/z): MNa+ (432).
##STR00241##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 7.35 (m, 4H), 5.70 (s, 1H), 4.50 (m, 2H), 3.00 (dd, J=6.0, 2.1 Hz, 2H), 1.50 (s, 3H).
MS (m/z): MH+ (319).
##STR00242##
Following the procedure described in Example 29, the title compounds were obtained as white solids.
MS (m/z): M+1 (409).
MS (m/z): M+1 (409)
##STR00243##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.60 (s, 1H), 8.15 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 5.65 (s, 1H), 3.20 (m, 2H), 3.05 (dd, J=6.0, 2.4 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (379).
##STR00244##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.85 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 5.20 (s, 1H), 2.80 (dd, J=7.8, 2.4 Hz, 2H), 1.60 (m, 1H), 1.55 (s, 3H). MS (m/z): MH+ (365).
##STR00245##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (m, 2H), 7.82 (s, 1H), 7.60 (m, 2H), 7.35 (m, 2H), 7.15 (m, 2H), 3.60 (dd, J=25.0 Hz, 12.0 Hz, 2H), 1.35 (s, 3H)
MS (m/z): M+1 (400).
##STR00246##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.70 (s, 1H), 8.80 (s, 1H), 8.60 (m, 1H), 8.10 (s, 1H), 8.00 (m, 2H), 7.80 (m, 1H), 7.35 (m, 1H), 6.00 (s, 1H), 3.35 (dd, J=5.7, 2.4 Hz, 2H), 1.65 (s, 3H). MS (m/z): MH+ (374).
##STR00247##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ7.80 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.60 (dd, J=30.0 Hz, 18.0 Hz, 2H), 1.50 (s, 3H), 1.20 (s, 3H).
MS (m/z): M+1 (288).
##STR00248##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.50 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.75 (m, 1H), 7.50 (s, 4H), 7.45 (m, 1H), 5.70 (s, 1H), 3.25 (dd, J=5.4, 2.7 Hz, 2H), 2.15 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (439).
##STR00249##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.50 (s, 1H), 8.80 (s, 1H), 8.00 (s, 1H), 7.75 (m, 1H), 7.65 (s, 4H), 7.45 (m, 1H), 5.80 (s, 1H), 3.20 (dd, J=5.4, 2.4 Hz, 2H), 1.60 (s, 3H). MS (m/z): MH+ (492).
##STR00250##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.80 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.95 (m, 1H), 7.75 (s, 1H), 7.55 (s, 4H), 5.75 (s, 1H), 3.30 (dd, J=5.4, 2.4 Hz, 2H), 2.20 (s, 2H), 1.60 (s, 3H). MS (m/z): MNa+ (468).
##STR00251##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.80 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 7.55 (d, J=1.0 Hz, 2H), 6.85 (d, J=1.0 Hz, 2H), 5.60 (s, 1H), 3.30 (dd, J=5.4, 2.4 Hz, 2H), 2.0 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (431).
##STR00252##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.75 (s, 1H), 8.15 (s, 1H), 8.00-7.75 (m, 4H), 7.40 (m, 1H), 7.25 (s, 1H), 5.80 (s, 1H), 3.25 (dd, J=5.4, 2.4 Hz, 2H), 2.20 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (431).
##STR00253##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.30 (s, 1H), 8.10 (s, 1H), 8.00 (m, 2H), 6.10 (s, 1H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.66 (s, 3H). MS (m/z): MH+ (385).
##STR00254##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.78 (br, s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 5.25 (br, s, 1H), 2.95 (abq, J=12.5 Hz, 2H), 1.58 (s, 3H), 1.15 (s, 9H).
MS (m/z): MH+ (353), MH− (351).
##STR00255##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.01 (d, J=7.0 Hz, 1H), 7.62 (s, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.10 (s, 1H), 5.48 (s, 1H), 3.25 (abq, J=12.5 Hz, 2H), 1.52 (s, 3H), 1.25 (s, 9H).
MS (m/z): MH+ (373), MH− (371).
##STR00256##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 99.18 (s, br, 1H), 8.11 (s, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 6.25 (s, 1H), 4.32 (q, J=8.5 Hz, 2H), 3.25 (abq, J=12.5 Hz, 2H), 1.62 (s, 3H), 1.45 (t, J=8.5 Hz, 3H).
MS (m/z): MH+ (369), MH− (367).
##STR00257##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.22 (s, br, 1H), 8.11 (s, 1H), 8.02 (d, J=6.5 Hz, 1H), 8.00 (d, J=6.5 Hz, 1H), 6.38 (s, 1H), 4.32 (q, J=8.5 Hz, 2H), 3.25 (abq, J=12.5 Hz, 2H), 1.61 (s, 3H), 1.48 (t, J=8.5 Hz, 3H).
MS (m/z): MH+ (389), MNa+ (411).
##STR00258##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.95 (s, br, 1H), 7.98 (s, 1H), 7.65 (m, 2H), 6.35 (s, br, 1H), 4.33 (q, J=7.8 Hz, 2H), 3.15 (abq, J=10.5 z, 2H), 1.58 (s, 3H), 1.48 (t, J=7.8 Hz, 2H).
MS (m/z): MH+ (423)
##STR00259##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (C6D6) δ8.95 (s, 1H), 7.62 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.35 (d, J=7.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.0 Hz, 1H), 4.95 (s, 1H), 2.80 (abq, J=15.6 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MH+ (504), MH− (502)
##STR00260##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.79 (s, br, 1H), 8.25 (s, 1H), 7.88 (d, J=6.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 1H), 7.55 (s, 4H), 5.68 (s, 1H), 3.35 (abq, J=12.5 z, 2H), 2.28 (s, 3H), 1.68 (s, 3H).
MS (m/z): MH+ (387).
##STR00261##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.20 (s, 1H), 7.88 (s, 1H), 7.45 (s, 2H), 6.82 (s, 1H), 3.05 (abq, J=12.5 Hz, 2H), 1.58 (s, 3H). MS (m/z): MH+ (273).
##STR00262##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.15 (s, br, 1H), 7.95 (s, 1H), 7.75 (m, 2H), 7.55 (s, 1H), 4.35 (abq, J=10.5 Hz, 2H), 3.85 (abq, J=12.5 Hz, 2H), 2.65 (m, J=8.5 Hz, 2H), 1.42 (s, 3H), 1.32 (t, J=8.5 Hz, 3H).
MS (CI) m/z MH+ (371).
##STR00263##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.32 (s, br, 1H), 8.12 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 6.45 (s, 1H), 3.15 (abq, J=10.5 Hz, 2H), 1.61 (s, 3H), 1.52 (s, 9H).
MS (m/z): MH+ (397).
##STR00264##
5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid tert-butyl ester (450 mg, 1.135 mmoL) in trifluoroacetic acid (2 mL) and DCM (2 mL) was stirred for 6 hrs at room temperature. The reaction mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil.
1H NMR (CDCl3) δ 12.5 (s, br, 1H), 9.11 (s, 1H), 8.09 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 3.25 (abq, J=12.5 Hz, 2H), 1.61 (s, 3H).
MS (m/z): MH+ (341)
##STR00265##
5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid (150 mg, 0.441 mmoL) in THF (2 mL) was treated dropwise with borane-THF complex (882 μL, 0.882 mmoL) at −78° C. over 10 min. The resulting solution was stirred for another 10 min. and then quenched with MeOH. The solvent was removed and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel using 2:1 hexanes:ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.65 (s, 1H), 8.25 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 5.50 (s, 1H), 4.25 (abq, J=10.5 Hz, 2H), 2.95 (abq, J=12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (327).
##STR00266##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (MeOD) δ8.21 (s, 1H), 8.10 (d, J=6.5 Hz, 1H), 7.88 (d, J=6.5 Hz, 1H), 3.30 (abq, J=12.5 Hz, 2H), 1.68 (s, 3H).
##STR00267##
Following the procedure described in Example 31, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.21 (s, br, 1H), 8.12 (s, 1H), 8.02 (s, 2H), 6.05 (s, br, 1H), 3.18 (abq, J=13.5 Hz, 2H), 1.62 (s, 3H)
MS (m/z): MH− (413)
##STR00268##
Following the procedure described in Example 31, the title compounds were obtained as white solids.
1H NMR (CDCl3) δ 9.42 (s, br, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.76 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.65 (t, J=7.8 Hz, 1H), 7.60 (t, J=8.5 Hz, 2H), 6.82 (s, 1H), 5.45 (s, 1H), 3.01 (abq, J=13.5 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (308), MNa+ (330).
1H NMR (CDCl3) 6 (1:1 isomers) 8.45 (s, 1H, isomer 1), 8.25 (s, 1H, isomer 2), 7.30˜7.75 (m, 9H, both isomers), 4.40 (m, 1H, isomer 1), 4.32 (m, 1H, isomer 2), 2.48 (m, 1H, isomer 1), 2.10 (m, 1H, isomer 2), 1.72 (m, 1H, isomer 1), 1.32 (m, 1H, isomer 2), 1.55 (s, 3H, isomer 1), 1.50 (s, 3H, isomer 2), 0.15 (s, 9H, isomer 1), 0.10 (s, 9H, isomer 2).
##STR00269##
Following the procedure described in Example 31, the title compounds were obtained as white solids.
1H NMR (CDCl3) δ 9.45 (s, br, 1H), 7.75 (d, J=7.8 Hz, 2H), 7.62 (d, J=7.8 Hz, 2H), 6.85 (s, 1H), 5.45 (s, br, 1H), 3.01 (abq, J=12.5 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (229), MNa+ (251), MH− (227)
1H NMR (CDCl3) 6 (2:1 isomers) 9.35 (s, 1H, isomer 1), 8.51 (s, 1H, isomer 2), 7.51˜7.70 (m, 4H, both isomers), 4.45 (m, 1H, isomer 1), 4.40 (m, 1H, isomer 2), 2.08 (m, 1H, both isomers), 1.72 (m, 1H, both isomers), 1.58 (s, 3H, isomer 1), 1.45 (s, 3H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).
##STR00270##
Following the procedure described in Example 31, the title compounds were obtained as white solids.
1H NMR (CDCl3) δ 7.55 (s, br, 1H), 7.32 (m, 2H), 7.25 (m, 2H), 7.12 (t, J=7.8 Hz, 1H), 6.98 (m, 4H), 6.72 (s, 1H), 5.25 (s, br, 1H), 4.40 (d, J=5.2 Hz, 2H), 2.88 (abq, J=12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (310), MNa+ (332), MH− (308)
1H NMR (CDCl3) 6 (1:1 isomers) 6.85˜7.36 (m, 9H, both isomers), 6.75 (s, 1H, isomer 1), 6.51 (s, 1H, isomer 2), 4.51 (m, 2H, both isomers), 4.40 (m, 1H, isomer 1), 4.35 (m, 1H, isomer 2), 2.32 (m, 1H, isomer 1), 2.00 (m, 1H, isomer 2), 1.65 (m, 1H, isomer 1), 1.58 (s, 3H, isomer 1), 1.50 (s, 3H, isomer 2), 1.32 (m, 1H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).
##STR00271##
Following the procedure described in Example 31, the title compounds were obtained as white solids.
1H NMR (CDCl3) δ7.90 (d, J=7.5 Hz, 2H), 7.72 (br, s, 1H), 7.42 (d, J=7.5 Hz, 2H), 6.78 (s, 1H), 5.28 (s, 1H), 4.50 (d, J=4.8 Hz, 2H), 3.15 (s, 3H), 2.98 (abq, J=12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (296), MNa+ (318), MH− (294) 3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid 3-methanesulfonyl-benzylamide:
1H NMR (CDCl3) 6 (1:1 isomers) 7.82 (m, 2H, both isomers), 7.40 (m, 2H, both isomers), 7.15 (s, 1H, isomer 1), 6.90 (s, 1H, isomer 2), 4.51 (m, 2H, both isomers), 4.40 (m, 1H, isomer 1), 4.32 (m, 1H, isomer 2), 2.32 (m, 1H, isomer 1), 1.92 (m, 1H, isomer 2), 1.62 (m, 1H, isomer 1), 1.58 (s, 3H, isomer 1), 1.50 (s, 3H, isomer 2), 1.28 (m, 1H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).
##STR00272##
A racemic mixture of 3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto a ChiralPak AD chiral HPLC column (50 mm I.D.×500 mm L) and eluted with 10% ethanol in heptane at the 70 mL/min flow rate. Two peaks were collected separately and were removed under vacuum to yield:
MS (CI) m/z 365(M+H+)
MS (CI) m/z 365(M+H+)
##STR00273##
The racemic mixture of 3-ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto a ChiralPak AD chiral HPLC column (50 mm I.D.×500 mm L) and eluted with 10% ethanol in heptane at the 70 mL/min flow rate. Two peaks were collected separately and were removed under vacuum to yield:
MS (CI) m/z 379(M+H+)
MS (CI) m/z 379(M+H+)
##STR00274##
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.5 g, 5.1 mmoL) in glacial acetic acid (5 mL) was treated with powder NaCNBH3 (750 mg, 12.7 mmoL) at room temperature. The reaction mixture was stirred for 1 hr. The reaction mixture was then neutralized with saturated NaHCO3 and extracted with ethyl acetate (3×). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil.
1H NMR (CDCl3) δ 9.89 (s, br, 1H), 8.11 (s, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 3.28 (t, J=8.5 Hz, 2H), 2.65 m, 2H), 1.61 (s, 3H).
MS (CI) m/z MH+ (299), MH− (297).
##STR00275##
3-Methyl-pyrazolidine-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (350 mg, 0.84 mmoL) in DCM (2 mL) was treated with Et3N (118 μL, 0.84 mmoL) and TFAA (117 μL, 0.84 mmoL) at 0° C. The reaction mixture was stirred for 30 min and then partitioned between saturated NaHCO3 and DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil, which was then purified by silica gel column using hexanes:ethyl acetate 1:1 as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.22 (s, br, 1H), 8.08 (s, 1H), 7.82 (s, 2H), 3.72 (m, 2H), 3.10 (m, 1H0, 2.05 (m, 1H), 1.65 (s, 3H).
MS (CI) m/z MNa+ (417), MH− (393).
##STR00276##
3-Methyl-pyrazolidine-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (410 mg, 1.38 mmoL) and (225 mg, 1.38 mmoL) in MeOH (5 mL) at room temperature was treated with NaCNBH3 (216 mg, 3.44 mmoL). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil, which was then purified by silica gel column using hexanes:ethyl acetate 1:1 as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 8.05 (s, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.62 (d, J=6.5 Hz, 1H), 7.52 (d, J=7.0 Hz, 2H), 7.25 (d, J=7.0 Hz, 2H), 3.75 (abq, J=12.5 Hz, 2H), 3.18 (m, 1H), 2.65 (m, 3H), 2.15 (s, 3H), 1.48 (s, 3H).
MS (m/z): MNa+ (468)
##STR00277##
LiHMDS (1.0 N in THF, 23.6 mmoL, 24 mL) was added dropwise into pyridine (11.8 mmoL, 1.11 g) in THF (10 mL) at 0° C. After 10 min, 2-methyl-acryloyl chloride (11.8 mmoL, 1.43 mL) was added into the reaction at 0° C. The reaction was then slowly warmed to room temperature. The solvent was removed and the residue was partitioned between Et2O and water. The Et2O layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, EtOAc as eluent) to yield the title compound as a reddish oil.
1H NMR (CDCl3) δ 8.45 (br, s, 1H), 8.22 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 5.68 (s, 1H), 5.26 (s, 1H), 1.89 (s, 3H).
##STR00278##
Following the procedure described in Example 1, the title compound was obtained as a grey solid.
1H NMR (CDCl3) δ 8.45 (s, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.61 (s, br, 1H), 7.34 (d, J=7.5 Hz, 1H), 5.88 (s, 1H), 5.55 (s, 1H), 2.05 (s, 3H).
##STR00279##
Following the procedure described in Example 1, the title compound was obtained as a grey solid.
1H NMR (CDCl3) δ 8.65 (s, 1H), 8.48 (d, J=8.5 Hz, 1H), 7.88 (s, br, 1H), 7.70 (d, J=8.5 Hz, 1H), 5.88 (s, 1H), 5.62 (s, 1H), 2.12 (s, 3H).
MS (m/z): MH+ (188).
##STR00280##
Following the procedure described in Example 29, the title compound was obtained as a pale solid.
1H NMR (CDCl3) δ 9.45 (br, s, 1H), 8.35 (d, J=7.5 Hz, 2H), 7.38 (d, J=7.5 Hz, 2H), 7.15 (d, J=6.5 Hz, 2H), 7.04 (d, J=6.5 Hz, 2H), 3.36˜3.22 (Abq, J=12.5 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MH+ (299)
##STR00281##
Following the procedure described in Example 31, the title compound was obtained as a white solid in pure form.
1H NMR (CDCl3) δ 9.05 (s, br, 1H), 8.25 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 5.55 (s, br, 1H), 2.72 (abq, J=12.5 Hz, 2H), 1.25 (s, 3H).
MS (m/z): MH+ (239)
##STR00282##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.90 (s, 1H), 8.55 (m, 1H), 8.15 (m, 1H), 7.30 (m, 1H), 6.10 (s, 1H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (307).
##STR00283##
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.21 (s, br, 1H), 8.75 (s, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 6.05 (s, 1H), 3.20 (abq, J=11.5 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MNa+ (320).
##STR00284##
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (193 mg, 0.76 mmoL) in xylene (5 mL) was treated with N-methyl-{4-(oxyimino-methyl)phenyl)acetamide (250 mg, 0.76 mmoL) (which may be prepared by known methods). The reaction mixture was then heated to 50° C. and stirred for 6 hrs. The solvent was removed and the residue was purified by silica gel column using 1:1 hexanes:ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.42 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.62 (t, J=6.4 Hz, 1H), 2.75 (m, 1H), 2.68 (s, 3H), 2.61 (m, 1H), 2.18 (s, 3H), 1.62 (s, 3H).
MS (m/z): MH+ (447), MNa+ (469), MH− (445).
##STR00285##
Following the procedure described in Example 108, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.45 (s, br, 1H), 8.12 (s, 1H), 8.01 (m, 2H), 7.45 (d, J=7.8 Hz, 2H), 7.38 (s, 1H), 7.18 (d, J=7.8 Hz, 2H), 3.61 (t, J=6.5 Hz, 1H), 2.81 (m, 1H), 2.68 (s, 3H), 2.61 (m, 1H), 2.18 (s, 3H), 1.62 (s, 3H).
MS (m/z): MH+ (467), MNa+ (489)
##STR00286##
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0 mmol) in CH2Cl2 (15 ml) was treated by TFA (3.0 ml) at 0° C. To the reaction mixture was then added H2O2 (30%, 1.0 ml, 10.0 mmol) dropwise. The reaction mixture was stirred overnight and quenched by NaHCO3, then extracted by ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using hexanes:ethyl acetate 4:1 as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 8.40 (br. 1H), 8.10-7.80 (m, 3H), 5.85 (s, 1H), 5.60 (s, 1H), 2.00 (s, 3H).
MS (m/z): MNa+ (293).
##STR00287##
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.0 g, 3.48 mmoL) was dissolved in 7N NH3/MeOH solution (10 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed to yield the title compound as pale yellow solid.
1H NMR (CDCl3) δ 9.58 (s, br, 1H), 8.15 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 3.42 (d, J=9.8 Hz, 1H), 2.65 (d, J=9.8 Hz, 1H), 1.48 (s, 3H)
MS (m/z): MH+ (288)
##STR00288##
BF3.Etherate (1.0 mmol) was added to a mixture of 2-methyl-oxirane-2carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (135 mg, 0.5 mmol) in acetonitrile (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched with NaHCO3, the organic layer was extracted with ethyl acetate, washed with brine and concentrated to yield a crude product. The crude product was purified on silica gel with ethyl acetate to yield the title compound as a solid.
1H NMR (CDCl3) δ 8.50 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.0 Hz), 1H), 4.00 (dd, J=105Ha, 15Ha, 2H), 2.10 (s, 3H), 1.70 (s, 3H)
MS (m/z): MH+ (312), MNa+ (334).
##STR00289##
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (100 mg, 0.35 mmoL) and acetic acid 4-formyl-phenyl ester (57 mg, 0.35 mmoL) in MeOH (5 mL) was stirred at room temperature for 2 hr. Then, a catalytic amount of pTSA (˜10 mg) was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by silica gel column using hexanes:ethyl acetate 2:1 as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.60 (s, br, 1H), 8.31 (s, br, 1H), 8.08 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 4.42 (br, s, 1H), 4.02 (abq, J=12.5 Hz, 2H), 2.18 (s, 3H), 1.55 (s, 3H).
MS (m/z): MH+ (433)
##STR00290##
Following the procedure described in Example 112, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 7.80 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.60 (dd, J=30.0 Hz, 18.0 Hz, 2H), 1.50 (s, 3H), 1.20 (s, 3H).
MS (m/z): MH+ (332), MNa+ (354)
##STR00291##
Following the procedure described in Example 112, the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 8.15 (s, 1H), 7.80 (dd, J=52.0 Hz, 9.0 Hz, 4H), 3.50 (dd, J=60.0 Hz, 21.0 Hz, 2H), 1.90 (s, 3H), 1.40 (s, 3H)
MS (m/z): M+H2O (262)
##STR00292##
Following the procedure described in Example 21, starting from N-[4-(ethyl-hydrazonomethyl)-phenyl]-acetamide, the title compound was prepared as a white solid.
MS (m/z): MH+ (240).
##STR00293##
Following the procedure described in Example 23, starting from 4-acetamido-N-(ethyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as an off-white solid.
MS (m/z): MH+ (458).
##STR00294##
3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1 mmoL) was reacted with a diazoethane/diethyl ether solution (10 mmoL) in dioxane for about 5 days. The reaction mixture was worked up by solvent evaporation and column chromatography separation. The title compound was isolated as a minor product, as a white solid.
1H NMR (CDCl3) δ 9.68 (s, 1H), 8.07 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 3.15 (m, 1H), 3.05 (abq, J=10.0 Hz, 1H), 2.80 (m, 1H), 2.71 (abq, J=10.0 Hz, 1H), 1.98 (s, 3H), 1.40 (s, 3H), 1.35 (t, J=9.5 hz, 3H)
MS (m/z): MH+ 339.
##STR00295##
2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 mL) was refluxed for 30 min. Excess thionyl chloride was removed in vacuo to yield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) in diethyl ether (50 mL) was added dropwise to the residue at −40° C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The diethyl ether layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as yellow solid.
1H NMR (CDCl3) δ 8.25 (br, s, 1H), 7.60 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.25 (s, 1H), 5.98 (s, 1H).
##STR00296##
Following the procedure described in Example 29, starting from N-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide and 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ9.18 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.82 (D, J=8.0 Hz, 1H), 7.05 (s, 1H), 3.62 (abq, J=9.0 Hz, 1H), 3.08 (abq, J=9.0 Hz, 1H)
MS (m/z): MH+ 419.
##STR00297##
Following the procedure described in Example 31 starting from N-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide and ethyl diazoacetate, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 9.28 (s, 1H), 8.10 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.70 (s, 1H), 4.32 (q, J=6.8 Hz, 2H), 3.72 (abq, J=8.5 Hz, 1H), 3.60 (abq, J=8.5 Hz, 1H), 1.35 (t, J=8.5 Hz, 3H)
MS (m/z): MH+ 423.
##STR00298##
##STR00299##
Following the procedure described in Example 47, starting from N-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide, the title compounds were prepared as off-white solids.
1H NMR (CDCl3) 6 diastereomer 1, 9.01 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 4.85 (m, 1H), 3.15 (m, 1H), 2.40 (m, 1H), 1.55 (d, J=9.5 Hz, 3H); diastereomer 2, 8.55 (s, 1H), 8.05 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 4.70 (m, 1H), 2.75 (m, 1H), 1.80 (m, 1H), 1.65 (d, J=10.0 Hz, 3H).
1H NMR (CDCl3) δ 9.75 (br, s, 1H), 8.15 (s, 1H), 7.98 (d, J=6.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 6.25 (s, 1H), 3.45 (abq, J=8.5 Hz, 1H), 3.25 (abq, J=8.5 Hz, 1H), 2.12 (s, 3H)
MS (m/z): MH+ 365.
##STR00300##
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (4.4 mmoL) in DCM (15 mL) was reacted with pyridine (6 mL) followed by trifluoroacetic anhydride (4.4 mmoL) at 0° C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was partitioned between DCM and water. The DCM layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. The crude material (the yellow oil) was purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as a yellow solid.
1H NMR (CDCl3) δ8.15 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 6.25 (s, 1H), 5.81 (s, 1H), 5.65 (s, 1H), 2.05 (s, 3H). MS (m/z): MH+ 351.
##STR00301##
Following the procedure described in Example 29, starting from N-(4-cyano-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-N-(2-methyl-acryloyl)-acetamide and 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ8.10 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 3.75 (d, J=10.5 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 1.85 (s, 3H)
MS (m/z): MNa+ 483
##STR00302##
Following the procedure described in Example 29, starting from N-(4-bromo-3-trifluoromethyl-phenyl)-2-methyl-acrylamide and 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCl3) δ 8.95 (s, 1H), 7.96 (s, 1H), 7.65 (s, 2H), 5.86 (s, 1H), 3.28 (abq, J=9.8 Hz, 1H), 3.10 (abq, J=9.8 Hz, 1H), 1.60 (s, 3H)
MS (m/z): MH+ 419.
##STR00303##
##STR00304##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (400 mg, 1.1 mmol) and Na2HPO4 (1.0 g, 7 mmol) in CH2Cl2 (10 ml) was treated with BF4.O(CH2CH3)3 (1M in CH2Cl2, 5.0 ml) at 0° C. The reaction mixture was warmed to room temperature, stirred overnight and then quenched with NaHCO3. CH2Cl2 was added to extract the product and the organic layer was then washed with brine and dried over Na2SO4. Upon the purification on silica gel (CH2Cl2:ethyl acetate: 10:1), the title compounds were obtained as white solids.
1H NMR (CDCl3) δ 9.10 (br, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 3.40-3.00 (m, 4H), 1.50 (s, 3H), 1.35 (m, 3H)
MS (m/z): MH+ 393
1H NMR (CDCl3) δ 7.85 (m, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 5.30 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 2.95 (m, 1H), 2.40 (m, 1H), 1.55 (m, 3H), 1.50 (s, 3H)
MS (m/z): MH+ 393
##STR00305##
##STR00306##
Following the procedure described in Example 126, starting from 3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, the title compounds were prepared as off-white solids.
NMR and MS data of the title compounds were the same as described in Example 126.
##STR00307##
##STR00308##
Following the procedure described in Example 126, starting from 3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, the title compounds were prepared as off-white solids.
NMR and MS data of the title compounds were the same as described in Example 126.
##STR00309##
##STR00310##
3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (2.5 mmoL) in DCM (25 mL) at 0° C. was treated with diethylpropyl amine (10 mmoL) followed by methyl triflate (2.5 mmoL). The reaction mixture was gradually warmed to room temperature and then stirred overnight. The reaction mixture was partitioned between DCM and water. The DCM layer was washed with saturated sodium bicarbonate, brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil, which was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compounds as off-white solids.
1H NMR (CDCl3) δ 9.02 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 3.32 (abq, J=9.5 Hz, 1H), 3.02 (abq, J=9.5 Hz, 1H), 3.01 (s, 3H), 1.52 (s, 3H)
MS (m/z): MH+ 379.
1H NMR (CDCl3) δ 8.21 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 4.36 (s, 3H), 3.52 (s, 3H), 3.36 (d, J=12.5 Hz, 1H), 3.10 (d, J=12.5 Hz, 1H), 1.52 (s, 3H)
MS (m/z): MH+ 393.
##STR00311##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in toluene (5 mL) was treated with PCl5 (1.2 mmoL) at 100° C. for 2 hrs. The solvent was removed and the residue was purified by column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid (3:2 diastereomers).
Major Diastereomer:
1H NMR (CDCl3) δ8.32 (s, 1H), 8.10 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 3.05 (abq, J=9.8 Hz, 1H), 2.25 (abq, J=9.8 Hz, 1H), 1.90 (s, 3H).
Minor Diastereomer
1H NMR (CDCl3) δ 8.62 (s, 1H), 8.11 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 2.90 (abq, J=9.8 Hz, 1H), 2.32 (abq, J=9.8 Hz, 1H), 1.88 (s, 3H).
MS, MH+, 399.
##STR00312##
Following the procedure described in Example 1, starting from 4-amino-5-iodo-2-trifluoromethyl-benzonitrile (known compound), the title compound was prepared as off-white solid.
1H NMR (CDCl3) δ 9.00 (s, 1H), 8.30 (br, 1H), 8.20 (s, 1H), 6.00 (s, 1H), 5.65 (s, 1H), 2.15 (s, 3H)
MS (m/z): MH− 379
##STR00313##
Following the procedure described in Example 29, starting from N-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.80 (s, 1H), 9.10 (s, 1H), 8.20 (s, 1H), 6.00 (s, 1H), 3.25 and 3.10 (abq, J=14.5 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ 491.
##STR00314##
Following the procedure described in Example 1, starting from 4-amino-2-ethyl-2-trifluoromethyl-benzonitrile (known compound), the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 8.60 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.5 Hz, H), 5.88 (s, 1H), 5.63 (s, 1H), 2.85 (q, J=9.0 Hz, 2H), 2.12 (s, 3H), 1.40 (t, J=9.0 Hz, 3H)
MS (m/z): MH+ 283.
##STR00315##
Following the procedure described in Example 29, starting from N-(4-cyano-2-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (MeOD) δ 9.50 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 5.90 (s, 1H), 3.30 and 3.05 (abq, J=12.0 Hz, 2H), 2.80 (m, 2H), 1.65 (s, 3H), 1.20 (m, 3H)
MS (m/z): MH+ 393
##STR00316##
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (936 mg, 3.0 mmol), CuI (I) (57 mg, 0.3 mmol), PdCl2(PPh3)2 (105.3 mg, 0.15 mmol), triethylamine (1.01 g, 10 mmol) and ethynyl-trimethyl-silane (450 mg, 4.5 mmol) were mixed in THF (30 ml). The reaction mixture was stirred at room temperature overnight. Tetrabutylammonium fluoride (1.0 M in THF, 3.0 ml, 3.0 mmol) was added to the reaction mixture, which was then stirred at room temperature for 20 mins. The reaction mixture was quenched by addition of H2O and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated to yield crude product 4-amino-5-ethynyl-2-trifluoromethyl-benzonitrile.
The crude product was mixed with Pd/C (0.3 g) in methanol (50 ml) with H2 (40 psi). The reaction was shaken on a Parr shaker at room temperature overnight. Upon separation on silica gel (100% CH2Cl2), the tile compound was obtained in as a colorless liquid.
1H NMR (CDCl3) δ 7.50 (s, 1H), 7.00 (s, 1H), 4.50 (br, 2H), 2.50 (m, 2H), 1.30 (m, 3H)
MS (m/z): MH+ 214
##STR00317##
Following the procedure described in Example 1, starting from 4-amino-6-ethyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 8.80 (s, 1H), 7.70 (br, 1H), 7.65 (s, 1H), 5.90 (s, 1H), 5.60 (s, 1H), 3.70 (m, 2H), 2.10 (s, 3H), 1.30 (m, 3H)
MS (m/z): MH− 283
##STR00318##
Following the procedure described in Example 29, starting from N-(4-cyano-6-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.30 (s, 1H), 8.80 (s, 1H), 7.55 (s, 1H), 5.90 (s, 1H), 3.25 and 3.10 (abq, J=14.0 Hz, 2H), 2.70 (m, 2H), 1.65 (s, 3H), 1.30 (m, 3H)
MS (m/z): MH+ 393
##STR00319##
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (1.5 mmoL), CuCN (1.7 mmoL) in NMP (10 mL) was heated at 150° C. for 4 hrs. The reaction mixture was passed through a pad of Celite. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a brown solid.
1H NMR (CDCl3) δ 7.82 (s, 1H), 7.15 (s, 1H), 5.45 (br, s, 2H)
MS (m/z): MH+ 212
##STR00320##
Following the procedure described in Example 1, starting from 4-amino-6-trifluoromethyl-isophthalonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.15 (s, 1H), 8.45 (br, s, 1H), 8.08 (s, 1H), 6.05 (s, 1H), 5.75 (s, 1H), 2.12 (s, 3H)
MS (m/z): MH+ 280
##STR00321##
Following the procedure described in Example 29, starting from N-(2,4-dicyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ10.10 (s, 1H), 9.10 (s, 1H), 8.10 (s, 1H), 6.45 (s, 1H), 3.30 and 3.10 (abq, J=14.0 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ 390
##STR00322##
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (6.24 g, 20.0 mmol), CuI (I) (380 mg, 2.0 mmol), K2CO3 (6.52 g, 40.0 mmol) and ethylthiol (1.25 g, 20.0 mmol) were mixed in ethanol (50 ml). The reaction mixture was refluxed overnight and then the solvent was removed under vacuum. Upon separation on silica gel (100% DCM), the tile compound was obtained as a colorless liquid.
1H NMR (CDCl3) δ 7.70 (s, 1H), 7.00 (s, 1H), 5.10 (br, 2H), 2.85 (m, 2H), 1.25 (m, 3H)
MS (m/z): MH2O+ 264
##STR00323##
Following the procedure described in Example 1, starting from 4-amino-5-ethylsulfanyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.10 (br, s, 1H), 9.05 (s, 1H), 7.88 (s, 1H), 5.98 (s, 1H), 5.60 (s, 1H), 2.95 (q, J=9.5 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J=9.5 Hz, 3H)
MS (m/z): MH+ 315
##STR00324##
Following the procedure described in Example 29, starting from N-(4-cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 8.30 (br, 1H), 7.35 (m, 1H), 7.10 (s, 1H), 6.80 (m, 1H), 5.10 (br, 1H), 3.25 and 3.10 (abq, J=11.0 Hz, 2H), 1.60 (s, 3H)
MS (m/z): MH+ 365
##STR00325##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-amide (150 mg, 0.35 mmol) in ethyl acetate was treated with Oxone® (2.0 g, pH=7-8, adjusted with saturated NaHCO3 and tetrabuylammonium hydrogensulfate (30 mg). The reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO3. The crude product was extracted with ethyl acetate twice, washed with brine and dried with Na2SO4. Upon purification on silica gel (CH2Cl2:EtOAc: 3:1), the title compound was obtained as a white solid.
1H NMR (CDCl3) δ 9.20 (s, 1H), 8.30 (s, 1H), 6.05 (s, 1H), 3.25 and 3.10 (abq, J=12.0 Hz, 2H), 3.15 (m, 2H), 1.65 (s, 3H), 1.30 (m, 3H). MS (m/z)
MH+ 457
##STR00326##
Following the procedure described in Example 141, starting from t-butyl thiol, the title compound was prepared as a brown solid.
1H NMR (CDCl3) δ 7.75 (s, 1H), 7.00 (s, 1H), 5.45 (br, 2H), 1.30 (s, 9H)
MS (m/z): MH2O 292
##STR00327##
Following the procedure described in Example 1, starting from 4-amino-5-tert-butylsulfanyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.65 (s, 1H), 9.15 (s, 1H), 7.95 (s, 1H), 6.00 (s, 1H), 5.65 (s, 1H), 2.10 (s, 3H), 1.35 (s, 9H)
MS (m/z): MH− 341
##STR00328##
Following the procedure described in Example 29, starting from N-(2-tert-butylsulfanyl-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ10.75 (s, 1H), 9.10 (s, 1H), 7.95 (s, 1H), 6.00 (s, 1H), 3.20 and 3.05 (abq, J=11.0 Hz, 2H), 1.65 (s, 3H), 1.30 (s, 9H)
MS (m/z): MH− 452
##STR00329##
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (312 mg, 1.0 mmol), CuI (I) (20 mg, 0.1 mmol), Cs2CO3 (652 mg, 2.0 mmol) and 1,10-phenanthroline (36 mg, 0.2 mmol) were mixed in methanol (20 ml). The reaction mixture was refluxed overnight and then the solvent was removed under vacuum. Upon separation on silica gel (100% CH2Cl2), the tile compound was obtained as a colorless liquid.
1H NMR (CDCl3) δ 7.05 (s, 1H), 6.90 (s, 1H), 4.50 (br, 2H), 3.90 (s, 3H)
MS (m/z): MH+ 216
##STR00330##
Following the procedure described in Example 1, starting from 4-amino-5-methoxy-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.00 (s, 1H), 8.40 (s, 1H), 7.26 (s, 1H), 5.90 (s, 1H), 5.60 (s, 1H), 4.00 (s, 3H), 2.10 (s, 3H)
##STR00331##
Following the procedure described in Example 29, starting from N-(4-cyano-2-methoxy-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.65 (br, 1H), 8.90 (s, 1H), 7.25 (s, 1H), 5.90 (s, 1H), 4.00 (s, 3H), 3.25 and 3.05 (abq, J=10.0 Hz, 2H), 1.60 (s, 3H)
MS (m/z): MH+ 395
##STR00332##
##STR00333##
4-Amino-2-trifluoromethyl-benzonitrile (10.5 mmoL), NCS (15.5 mmoL) in MeOH (50 mL) at 0° C. was stirred for 2 hrs. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with sodium thiosulfate, water and brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compounds as brown solids.
H NMR (CDCl3) δ 7.65 (s, 1H), 7.02 (s, 1H), 4.90 (br, s, 2H)
MS (m/z): MH+ 221.
1H NMR (CDCl3) δ 7.61 (s, 1H), 5.32 (br, s, 2H)
MS (m/z): MH+ 256.
##STR00334##
Following the procedure described in Example 1, starting from 4-amino-5-chloro-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.95 (s, 1H), 7.52 (s, 1H), 5.80 (br, s, 1H), 5.65 (s, 1H), 5.60 (s, 1H)
MS (m/z): MH+ 289
##STR00335##
Following the procedure described in Example 29, starting from N-(2-chloro-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 9.88 (br, s, 1H), 9.05 (s, 1H), 7.90 (s, 1H), 3.31 (abq, J=10.5 Hz, 1H), 3.15 (abq, J=11.0 Hz, 1H), 1.68 (s, 3H)
MS (m/z): MH+ 399
##STR00336##
Following the procedure described in Example 1, starting from 4-amino-3,5-dichloro-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.88 (s, 1H), 7.50 (s, 1H), 6.02 (s, 1H), 5.68 (s, 1H), 2.11 (s, 3H)
MS (m/z): MH+ 324
##STR00337##
##STR00338##
##STR00339##
Following the procedure described in Example 29, starting from N-(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compounds were prepared as off-white solids.
1H NMR (CDCl3) δ 8.82 (s, 1H), 7.71 (s, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 2.85 (m, 1H), 1.35 (s, 3H)
MS (m/z): MH+ 434.
1H NMR (CDCl3) δ 9.08 (s, 1H), 7.50 (s, 1H), 5.72 (s, 1H), 3.25 (abq, J=10.5 Hz, 1H), 2.85 (abq, J=10.5 Hz, 1H), 1.58 (s, 3H)
MS (m/z): MH+ 434.
1H NMR (CDCl3) δ 7.88 (s, 1H), 5.62 (m, 1H), 3.75 (m, 2H), 3.58 (abq, J=12.5 Hz, 1H), 2.92 (abq, J=12.5 Hz, 1H), 1.68 (s, 3H)
MS (m/z): MH+ 516
##STR00340##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.5 mmoL) in DCM (˜20 mL) was reacted with pyridine (2.0 mmoL) followed by trifluoroacetic anhydride (1.5 mmoL) which was added dropwise at 0° C. The reaction mixture was then stirred for 2 hrs. The solvent was removed and the residue was partitioned between DCM and water. The organic layer was washed with saturated sodium bicarbonate, water and then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compound as an off-white solid.
1H NMR (CDCl3) δ 9.72 (s, 1H), 8.08 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 4.35 (abq, J=12.5 Hz, 1H), 3.10 (abq, J=12.5 Hz, 1H), 2.01 (s, 3H)
MS (m/z): MH+ 461
##STR00341##
2-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in DMF (10 mL) was treated with NaH (60%, 1.2 mmoL) followed by CH3I (1.1 mmoL) at 0° C. The reaction mixture was stirred for 1 hr and then warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate, water and then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compound as an off-white solid.
1H NMR (CDCl3) δ 7.80 (m, 1H), 7.60 (s, 1H), 7.45 (m, 1H), 3.40 (s, 3H), 3.35 and 2.90 (abq, J=14.0 Hz, 2H), 3.20 (m, 1H), 3.00 (m, 1H), 1.50 (s, 3H), 1.15 (t, J=3.0 Hz, 3H)
MS (m/z): MH+ 390
##STR00342##
Following the procedure described in Example 27, starting from acetaldehyde oxime, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 8.65 (s, 1H), 7.95 (s, 1H), 7.40 (m, 2H), 3.40 and 2.95 (abq, J=14.0 Hz, 2H), 2.00 (s, 3H), 1.70 (s, 3H)
MS (m/z): MH+ 390
##STR00343##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (15 mmoL) and Lawesson's agent (15 mmoL) in toluene (100 mL) was refluxed for 6 hrs until the solution turned clear. The reaction mixture was then cooled and some precipitate was observed. The solid was removed by filtration and the filtrate was concentrated to yield crude product as a green oil. The green oil was purified by silica gel column chromatography using DCM and ethyl acetate as eluent to yield the title compound as a green solid.
1H NMR (CDCl3) δ 11.05 (s, 1H), 8.45 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 5.95 (br, s, 1H), 3.40 (abq, J=9.5 Hz, 1H), 3.21 (abq, J=9.5 Hz, 1H), 1.85 (s, 3H)
MS (m/z): MH+ 381
##STR00344##
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (10 mmoL), K2CO3 (15 mmoL) in acetone was treated with CH3CH21 (10 mmoL) at room temperature. The reaction mixture was heated gently and then stirred at 50° C. for 1 hr. The solid was filtrated and the filtrate was concentrated to yield crude product as a brown oil, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a colorless oil.
1H NMR (CDCl3) δ7.80 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 3.51 (abq, J=12.5 Hz, 1H), 2.88 (abq, J=12.5 Hz, 1H), 2.35 (q, J=8.5 Hz, 2H), 1.08 (t, J=8.5 Hz, 3H)
MS (m/z): MH+ 409
##STR00345##
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (2 mmoL) in dioxane (15 mL) was treated with ethyl amine/THF solution (˜3 mmoL) and K2CO3 (2 mmoL) at 70° C. The reaction mixture was then stirred 4 hr. The solid was removed by filtration. The filtrate was concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 7.62 (d, J=7.5 Hz, 1H), 7.10 (s, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.15 (s, 1H), 5.78 (s, 1H), 3.20 (abq, J=9.5 Hz, 1H), 2.95 (abq, J=9.5 Hz, 1H), 2.85 (q, J=8.0 Hz, 2H), 1.48 (s, 3H), 1.30 (t, J=8.0 Hz, 3H)
MS (m/z): MH+ 392
##STR00346##
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (1 mmoL) in DMF (5 mL) was treated with N-hydroxamine hydrochloride salt (1 mmoL) and K2CO3 (2 mmoL) at room temperature. The reaction mixture was then stirred for 4 hr. The solid was removed by filtration. The filtrate was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 8.20 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 6.85 (d, J=7.5 Hz, 1H), 5.92 (s, 1H), 3.25 (abq, J=8.8 Hz, 1H), 2.82 (abq, J=8.8 Hz, 1H), 1.50 (s, 3H)
MS (m/z): MH+ 380
##STR00347##
Following the procedure described in Example 162, starting from O-methyl-hydroxylamine and N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.72 (d, J=6.5 Hz, 1H), 7.22 (s, 1H), 7.11 (d, J=6.5 Hz, 1H), 6.12 (s, 1H), 3.60 (s, 3H), 3.50 (abq, J=8.5 Hz, 1H), 2.95 (abq, J=8.5 Hz, 1H), 1.58 (s, 3H)
MS (m/z): MH+ 394
##STR00348##
##STR00349##
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (1.2 mmoL) in dioxane (10 mL) was treated with ammonia in MeOH (7N solution, ˜10 mL) in a sealed tube. The reaction mixture was heated to 100° C. for 4 hrs. The solvent was removed and the residue was purified by silica gel column chromatography using ethyl acetate and methanol as eluent to yield the title compounds as white solids.
1H NMR (CDCl3) δ 9.50 (br, s, 1H), 8.11 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 5.63 (s, 1H), 3.05 (abq, J=10.5 Hz, 1H), 2.95 (abq, J=10.5 Hz, 1H), 1.58 (s, 3H)
MS (m/z): MH+ 364.
MS (m/z): MH+ 379.
##STR00350##
Following the procedure described in Example 164, starting from methyl amine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.60 (d, J=8.5 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.05 (s, 1H), 5.60 (s, 1H), 3.15 (abq, J=10.5 Hz, 1H), 2.85 (abq, J=10.5 Hz, 1H), 2.90 (s, 3H), 1.45 (s, 3H)
MS (m/z): MH+ 378
##STR00351##
Following the procedure described in Example 164, starting from diethyl amine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.31 (s, 1H), 3.70 (q, J=5.5 Hz, 1H), 3.55 (abq, J=10.5 Hz, 1H), 3.45 (q, J=5.5 Hz, 1H), 3.05 (abq, J=10.5 Hz, 1H), 1.55 (s, 3H), 1.20 (t, J=8.5 Hz, 6H)
MS (m/z): MH+ 420
##STR00352##
Following the procedure described in Example 164, starting from pyrrolidine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.71 (d, J=7.0 Hz, 1H), 7.22 (s, 1H), 7.08 (d, J=7.0 Hz, 1H), 3.77 (t, J=6.0 Hz, 1H), 3.62 (t, J=6.0 Hz, 1H), 3.60 (abq, J=9.5 Hz, 1H), 3.05 (abq, J=9.5 Hz, 1H), 1.95˜1.70 (m, 4H), 1.58 (s, 3H)
MS (m/z): MH+ 418
##STR00353##
Following the procedure described in Example 164, starting from methylsulfonamide and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 7.85 (br, s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.58 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.05 (br, s, 1H), 3.62 (abq, J=10.5 Hz, 1H), 3.32 (abq, J=10.5 Hz, 1H), 1.61 9s, 3H)
MS (m/z): MH+ 442
##STR00354##
Following the procedure described in Example 29, starting from 5-nitro-2-(2-methyl-acryloylamino)-benzoic acid methyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCl3) δ 8.95 (d, J=7.5 Hz, 1H), 8.90 (s, 1H), 8.48 (d, J=7.5 Hz, 1H), 6.80 (s, 1H), 5.61 (s, 1H), 4.01 (s, 3H), 3.10 (abq, J=10.5 Hz, 1H), 2.90 (abq, J=10.5 Hz, 1H), 1.55 (s, 3H)
MS (m/z): MH+ 307
##STR00355##
Following the procedure described in Example 159, starting from 3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (3,4-dichloro-phenyl)-amide, the title compound was prepared as a green oil.
1H NMR (CDCl3) δ10.70 (s, 1H), 8.10 (s, 1H), 7.65 (m, 1H), 7.45 (m, 1H), 5.80 (s, 1H), 3.30 and 3.15 (abq, J=13.0 Hz, 2H), 1.80 (s, 3H)
MS (m/z): MH+ 357
##STR00356##
Following the procedure described in Example 160, starting from 3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (3,4-dichloro-phenyl)-amide, the title compound was prepared as a colorless oil.
1H NMR (CDCl3) δ 7.40 (m, 1H), 7.00 (s, 1H), 6.80 (m, 1H), 6.60 (br, 1H), 5.30 (s, 1H), 3.50 and 2.80 (abq, J=14.0 Hz, 2H), 2.30 (m, 2H), 1.60 (s, 3H), 1.00 (m, 3H)
MS (m/z): MH+ 385
3(R)-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide
##STR00357##
Following the procedure described in Example 159, starting from 3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (3-trifluoromethyl-4-cyano-phenyl)-amide, the title compound was prepared as a green oil.
NMR and MS data are the same as described in Example 159.
##STR00358##
Following the procedure described in Example 160, starting from 3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, the title compound was prepared as a colorless oil.
NMR and MS data are the same as described in Example 160.
##STR00359##
Following the procedure described in Example 159, starting from 3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (3-trifluoromethyl-4-cyano-phenyl)-amide, the title compound was prepared as a green oil.
NMR and MS data are the same as described in Example 159.
##STR00360##
Following the procedure described in Example 160, starting from 3-(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, the title compound was prepared as a colorless oil.
NMR and MS data are the same as described in Example 160.
##STR00361##
Following the procedure described in Example 126, starting from N-(4-cyano-3-trifluoromethyl-phenyl)-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as a colorless oil.
1H NMR (CDCl3) δ 7.75 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.08 (D, j=7.5 Hz, 1H), 3.50 (m, 2H), 3.28 (abq, J=12.5 Hz, 1H), 2.85 (abq, J=12.5 hz, 1H), 2.48 (m, 2H), 1.50 (s, 3H), 1.35 (t, J=9.5 Hz, 3H), 1.28 (t, J=9.5 Hz, 3H)
MS (m/z): MH+ 437
##STR00362##
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethyl-3-(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (0.7 mmoL) in dioxane (5 mL) was treated with K2CO3 (1.4 mmoL) and NH2CN (1.0 mmoL) at 80° C. for 2 hr. The reaction mixture was then filtrated through a pad of Celite. The filtrate was concentrated and purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 9.25 (br, s, 1H), 8.05 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 3.40 (abq, J=11.5 Hz, 2H), 3.28 (m, 1H), 3.05 (m, 1H), 1.90 (s, 3H), 1.55 (t, J=85 Hz, 3H)
MS (m/z): MH+ 417
##STR00363##
3-Hydroxy-2-methyl-2-(2,2,2-trifluoro-acetylamino)-propionic acid (3.2 mmoL) in DMA (10 mL) was treated dropwise with thionyl chloride (4.5 mmoL) at 0° C. for 30 min. To the resulting solution was added 4-amino-2-trifluoromethyl-benzonitrile (3.2 mmoL) in DMA (5 mL) followed by TEA (5 mmoL). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtrated and concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCl3) δ 8.62 (s, 1H), 8.05 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 7.32 (d, J=6.8 Hz, 1H), 4.65 (abq, J=8.5 Hz, 1H), 4.45 (abq, J=8.5 Hz, 1H), 1.55 (s, 3H)
##STR00364##
Following the procedure described in Example 178, starting from 2-tert-butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid (prepared by literature known method), the title compound was prepared as a white solid.
1H NMR (CDCl3) δ 8.31 (br, s, 1H), 8.05 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 6.01 (s, 1H), 4.65 (d, J=8.0 Hz, 1H), 4.23 (d, J=8.0 Hz, 1H), 1.68 (s, 3H)
MS (m/z): MH+ 314
Mature (150 to 200 g) castrated male Sprague Dawley rats (Charles River) were treated once daily for 14 days with test compound (usually administered by oral gavage at up to the desired dosage, up to 30 mg/kg in a volume of 1 mL, in 30% cyclodextrin or 0.5% methylcellulose vehicle), or with testosterone propionate (administered subcutaneously by injection at the nape of the neck at 5 mg/kg, in a volume of 0.1 mL in sesame oil), or with vehicle (1 mL of 30% cyclodextrin or 0.5% methylcellulose, given orally). On the fifteenth day, the rats were euthanized by asphyxiation in carbon dioxide. Ventral prostates and levator ani muscles were removed and their wet weights determined.
Test compound activity was determined as the percent stimulation of tissue weight, with the vehicle-treated control group set to zero percent and the testosterone alone-treated control group set to 100%. A compound was designated as agonist active if it produced greater than or equal to 20% stimulation of levator ani at 30 mg/kg.
Representative compounds of the present invention were tested according to the procedure described, with results as listed in Table 10 below. For the compounds listed in Table 10 as “inactive”, one skilled in the art will recognize that said compounds may or may not have shown an effect on prostate and/or vesical weight, rather they are listed herein as “inactive” as they did not meet the specified criteria defined above. A designation of “toxic” indicates that the compound exhibited toxicity in the rats tested.
TABLE 10
% Prostate
% levator ani
ID #
Stimulation
Stimulation
8
active
active
9
inactive
inactive
11
inactive
inactive
15
inactive
inactive
17
inactive
inactive
27
inactive
inactive
30
inactive
active
33
inactive
active
34
inactive
inactive
35
active
active
36
inactive
active
37
inactive
active
38
inactive
inactive
39
inactive
inactive
40
inactive
inactive
41
inactive
inactive
43
inactive
active
44
inactive
inactive
45
inactive
inactive
46
inactive
inactive
47
inactive
inactive
48
inactive
inactive
73
inactive
inactive
74
active
active
75
inactive
inactive
76
inactive
inactive
77
inactive
inactive
78
inactive
inactive
79
inactive
inactive
83
inactive
inactive
84
inactive
inactive
85
inactive
active
86
inactive
active
87
active
active
89
inactive
inactive
90
inactive
inactive
91
inactive
inactive
92
inactive
inactive
98
active
active
99
active
active
100
inactive
active
102
inactive
inactive
107
inactive
inactive
110
active
inactive
111
inactive
inactive
112
inactive
active
113
inactive
inactive
114
inactive
inactive
115
inactive
inactive
116
active
active
118
toxic
toxic
119
inactive
active
120
active
active
123
inactive
active
124
active
active
125
active
active
126
active
active
127
active
active
128
inactive
inactive
129
inactive
inactive
130
active
active
133
inactive
active
134
inactive
inactive
138
inactive
inactive
139
inactive
inactive
140
inactive
active
142
inactive
inactive
202
active
active
205
inactive
active
206
active
active
207
active
active
208
active
active
209
inactive
inactive
210
inactive
active
211
inactive
inactive
212
active
active
214
inactive
inactive
215
inactive
inactive
217
inactive
inactive
218
active
active
Immature (approximately 50 g) castrated male Sprague Dawley rats (Charles River) were treated once daily for five days with test compound (usually given orally at 40 mg/kg in a volume of 0.3 mL, in 30% cyclodextrin or 0.5% methylcellulose vehicle) and with testosterone propionate (given subcutaneously by injection at the nape of the neck at 2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, the rats were euthanized by asphyxiation in carbon dioxide. Ventral prosatates and seminal vesicles were removed and their wet weights determined. Test compound activity was determined as the percent inhibition of testosterone-enhanced tissue weights, with a vehicle-treated control group set to zero percent and a testosterone alone-treated control group set to 100%.
A test compound was said to be “active” if the non weight adjusted prostate weight was ≦40 mg or the % Inhibition prostate weight, body weight adjusted was ≧60% @ 2 mg/day dosage. ID50's, if determined, of ≦20 mg/day also indicated an active compound.
Representative compounds of the present invention were tested according to the procedure described, with results as listed in Table 11 below. For the compounds listed in Table 11 as “inactive”, one skilled in the art will recognize that said compounds may or may not have shown an effect on prostate and/or vesical weight, rather they are listed herein as “inactive” as they did not meet the specified criteria defined above.
TABLE 11
Inhibition of prostate
Inhibition of seminal vesicle
(non-weight prostate
(non-weight seminal vesicle
ID #
weight, mg)
weight, mg)
1
active
active
2
active
active
3
active
active
4
active
active
5
active
active
6
active
active
7
active
inactive
8
active
inactive
9
active
inactive
10
active
active
11
inactive
inactive
12
inactive
inactive
13
active
active
14
active
active
15
inactive
inactive
24
inactive
inactive
25
active
active
42
active
active
49
active
active
112
inactive
inactive
113
inactive
inactive
120
active
active
124
inactive
inactive
127
active
active
128
active
active
129
inactive
inactive
133
inactive
active
138
inactive
inactive
139
active
active
140
inactive
inactive
141
inactive
inactive
142
inactive
active
143
inactive
inactive
205
active
active
214
inactive
inactive
As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 95 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
Zhang, Xuqing, Sui, Zhihua, Li, Xiaojie
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